Osmotic delivery system, osmotic delivery system semipermeable body assembly, and method for controlling delivery rate of beneficial agents from osmotic delivery systems

ABSTRACT

Osmotic delivery system semipermeable body assemblies that control the delivery rate of a beneficial agent from an osmotic delivery system incorporating one of the semipermeable body assemblies. A semipermeable body assembly or plug includes a semipermeable body which is positionable in an opening of an osmotic delivery system. The semipermeable body has a hollow interior portion having a size selected to obtain a predetermined liquid permeation rate through the semipermeable body. Because the beneficial agent in the osmotic delivery system is delivered at substantially the same rate the osmotic agent imbibes liquid which has permeated through the plug from a surrounding environment, the liquid permeation rate through the plug controls the delivery rate of the beneficial agent from the osmotic delivery system. The liquid permeation rate through a semipermeable body may be varied to control the delivery rate of beneficial agent from an osmotic delivery system by changing the thickness of the semipermeable body or by changing an amount of surface area of the semipermeable body that is exposed to liquid when the osmotic delivery system is located in a liquid environment of use.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/053,689 filed Jul. 25, 1997, pursuant to 35 U.S.C. §119(e).

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to osmotic delivery systems fordelivering beneficial agents, and more particularly, to osmotic deliverysystem semipermeable body assemblies which control the delivery rate ofa beneficial agent from an osmotic delivery system incorporating one ofthe semipermeable body assemblies.

[0004] 2. Description of the Related Art

[0005] Controlled delivery of beneficial agents, such as drugs, in themedical and veterinary fields has been accomplished by a variety ofmethods. One method for controlled prolonged delivery of beneficialagents involves the use of osmotic delivery systems. These devices canbe implanted to release beneficial agents in a controlled manner over apreselected time or administration period. In general, osmotic deliverysystems operate by imbibing liquid from the outside environment andreleasing corresponding amounts of the beneficial agent.

[0006]FIG. 1 illustrates a cross sectional view of a known osmoticdelivery system 20. The osmotic delivery system 20, commonly referred toas an “osmotic pump,” generally includes some type of a capsule orenclosure 22 having a semipermeable portion which may selectively passwater into an interior of the capsule which contains a water-attractingosmotic agent 24. In the known osmotic delivery system illustrated inFIG. 1, the walls of the capsule 22 are substantially impermeable toitems within and outside the capsule, and the plug 26 acts as thesemipermeable portion. The difference in osmolarity between thewater-attracting agent 24 and the exterior of the capsule causes waterto pass through the semipermeable portion of the capsule which in turncauses the beneficial agent 23 to be delivered from the capsule 22through the delivery port 29. The water-attracting agent 24 may be thebeneficial agent delivered to the patient; however, in most cases suchas that illustrated in FIG. 1, a separate osmotic agent is usedspecifically for its ability to draw water into the capsule 22.

[0007] When a separate osmotic agent 24 is used, the osmotic agent maybe separated from the beneficial agent 23 within the capsule 22 by amovable dividing member or piston 28. The structure of the capsule 22 issuch that the capsule does not expand when the osmotic agent 24 takes inwater and expands. As the osmotic agent 24 expands, it causes thebeneficial agent 23 to be discharged through the orifice 29 at the samerate as the liquid, which is typically water, enters the osmotic agent24 by osmosis. Osmotic delivery systems may be designed to deliver abeneficial agent at a controlled constant rate, a varying rate, or in apulsatile manner.

[0008] In the known osmotic delivery system 20 illustrated in FIG. 1, anosmotic tablet is used as the osmotic agent 24 and is placed inside thecapsule 22. The membrane plug 26 is placed in an opening in the capsule22 through which the tablet 24 and piston 28 were inserted. Knownmembrane plugs 26 are typically a cylindrical member with ribs, andoperate in the same manner as a cork. These membrane plugs 26 seal theinterior of the capsule from the exterior environment, essentiallypermitting only certain liquid molecules from the environment of use topermeate through the membrane plug into the interior of the capsule 22.The rate that the liquid permeates through the membrane plug 26 controlsthe rate at which the osmotic agent 24 expands and drives a desiredconcentration of beneficial agent 23 from the delivery system 20 throughthe delivery orifice 29. The rate of delivery of the beneficial agentfrom the osmotic delivery system 20 may be controlled by varying thepermeability coefficient of the membrane plug 26.

[0009] By varying the permeability coefficient of the membrane plug 26,the liquid permeation rate through the membrane is controlled. Osmoticdelivery systems requiring a high beneficial agent delivery ratetypically use membrane plugs having high permeability coefficients.Osmotic delivery systems requiring a low beneficial agent delivery rateuse membrane plugs having low permeability coefficients. Thepermeability coefficient is dependent on the particular material orcombination of materials used in each membrane plug 26. Thus, the knownosmotic delivery system 20 illustrated in FIG. 1, which includes amembrane plug 26, may control the delivery rate of the beneficial agent23 by forming the same configuration plug 26 from differentsemipermeable materials having permeability coefficients correspondingto the desired beneficial agent delivery rate. One problem associatedwith obtaining different permeation rates in this manner is that adifferent membrane material must be used for every system which has adifferent desired beneficial agent delivery rate, requiring the purchaseof many different membrane materials and manufacture of many differentmembrane plugs 26.

[0010] Although the osmotic delivery device illustrated in FIG. 1delivers consistent and reproducible beneficial agent delivery rates, itis not possible to easily alter the beneficial agent release rate fromthe osmotic delivery device; a new membrane plug must be manufacturedand incorporated into the device for each application. In manyinstances, it is desirable to easily increase or decrease the beneficialagent release rate from the osmotic delivery device. For example, therelease rate for some drugs should be increased or decreased for osmoticdelivery devices that are to be implanted if the patient is overweightor underweight. Additionally, many disease treatment regimens requiredose titration to optimize therapeutic response to the beneficial agent,requiring that the beneficial agent release rate be adjusted inaccordance with the patient's efficacious response. It is not possibleto easily adjust the beneficial agent release rate from current osmoticdelivery devices, such as that illustrated in FIG. 1.

[0011] Many osmotic delivery systems which use membrane plugs, such asthat illustrated in FIG. 1, must administer beneficial agents at rapiddelivery rates over a short period of time. These known systems usemembrane materials having high permeability coefficients. i.e., highliquid uptake semipermeable materials. In general, high liquid uptakesemipermeable materials are those that have greater than 60% wateruptake, where % water uptake=100×(wet weight−dry weight)/dry weight.Thus, low uptake semipermeable materials have equal or less than 60%water uptake.

[0012] A dramatic problem associated with membrane plugs made from highliquid uptake semipermeable materials is that the membrane plug materialhas a tendency to absorb liquid and swell as the liquid from thesurrounding environment permeates through the membrane. This isproblematic because when the membrane plug overly swells, it exertsforces on the walls of the enclosure. Such forces may rupture theenclosure and allow the beneficial agent, osmotic agent or other itemswithin the interior of the enclosure to escape to the environment ofuse. Furthermore, the membrane plug may become dislodged from thesystem, which is especially hazardous with implantable delivery systems.Because of biocompatibility and delivery rate considerations, highliquid uptake membrane materials often must be used in osmotic deliverysystems destined for human implantation; consequently, there is a needfor osmotic delivery systems having membrane plugs which remain intactin the capsule during all phases of delivery.

[0013] Even if the membrane plug does not dislodge from the capsule,some high liquid uptake membrane plugs permit the osmotic agent to leakfrom the capsule because the membrane materials are biologicallyunstable. For instance, some semipermeable membranes having highpermeability coefficients, such as organic polymer membranes, areunstable in biological environments and may degrade over time,permitting fluids, crystals, or powder within the interior of thecapsule to leak to the environment of use. In some instances, theosmotic agent within the capsule may be harmful to the recipients ofimplantable delivery system, especially if released as a bolus, i.e.,all at once at a single location.

[0014] To ensure that the high liquid uptake membrane plug remainsintact within the delivery system capsule and seals the interior of thecapsule from the environment of use, some osmotic delivery systems useglues or adhesives with such high liquid uptake membrane plugs toprevent the capsule from leaking and to ensure that the membrane plugremains in place. Besides adding a manufacturing step and increasingcosts, applying an adhesive to the membrane plugs may problematicallyaffect the rate of permeation.

[0015] Still another problem associated with these high uptake membraneplugs is that the enclosure of the osmotic delivery system must be madesufficiently strong to withstand the greater forces exerted on theenclosure walls when the membrane plug expands radially.

[0016] Because of the above-identified problems associated with currentosmotic delivery system membrane plugs, it is costly and particularlydifficult to administer beneficial agents from osmotic delivery systemsat different desired delivery rates. Known membrane plug designs controlthe permeation rate of the membrane and the beneficial agent deliveryrate of the osmotic delivery system by selecting a different materialmembrane plug for each application requiring a particular beneficialagent administration rate. Additionally, current high liquid uptakemembrane plugs may dislodge or leak, and may be unstable in biologicalenvironments, causing items in the interior of delivery capsule toharmfully leak to the environment of use. These problems associated withcurrent osmotic drug delivery systems having known membrane plugs havecreated a need for a solution.

SUMMARY OF THE INVENTION

[0017] One object of the present invention is to provide an osmoticdelivery system semipermeable body assembly which controls the liquidpermeation rate through the semipermeable body assembly by varying thesize of a hollow interior portion or recess within the semipermeablebody of the semipermeable body assembly.

[0018] Another object of the present invention is to provide an osmoticdelivery system semipermeable body assembly which lessens the need touse high liquid uptake semipermeable materials for the membrane body ofthe semipermeable body assembly.

[0019] Another object of the present invention is to provide an osmoticdelivery system semipermeable body assembly which permits relativelyfast liquid permeation rates through semipermeable body materials madefrom relatively low permeability coefficient materials.

[0020] Still another object of the present invention is to provideosmotic delivery system semipermeable body assemblies having adjustableliquid permeation rates, even though the semipermeable bodies of theassemblies are made from one semipermeable material.

[0021] Yet another object of the present invention is to provide anosmotic delivery system semipermeable body assembly which helps preventleakage from the interior of an osmotic delivery system.

[0022] Another object of the present invention is to provide an osmoticdelivery system semipermeable body assembly which lessens the need touse glues or adhesives to keep the items within the osmotic deliverysystem from leaking to the environment of use.

[0023] Another object of the present invention is to provide an osmoticdelivery system which incorporates an osmotic delivery systemsemipermeable body assembly according to the present invention.

[0024] Still another object of the present invention is to provide amethod of controlling the delivery rate of a beneficial agent from anosmotic delivery system that incorporates an osmotic delivery systemsemipermeable body assembly according to the present invention.

[0025] Another object of the present invention is to provide a method ofchanging or altering a liquid permeation rate through a semipermeablebody of an osmotic delivery system.

[0026] Still another object of the present invention is to provide amethod of easily changing a liquid permeation rate through asemipermeable body of an osmotic delivery system.

[0027] Yet another object of the present invention is to provide anosmotic system having a semipermeable body having a liquid permeationrate that may be easily changed.

[0028] Still another object of the present invention is to increase theliquid permeation rate through semipermeable bodies of osmotic deliverysystem semipermeable body assemblies by increasing the surface area ofthe semipermeable body that is immediately exposed to liquid when theosmotic delivery system is located in a liquid environment of use.

[0029] The present invention strives to address the disadvantages ofknown osmotic delivery systems by providing: an osmotic delivery systemsemipermeable body assembly or plug for controlling a delivery rate of abeneficial agent from an osmotic delivery system; an osmotic deliverysystem incorporating the plug; a method of controlling the delivery rateof a beneficial agent from an osmotic delivery system with the plug; amethod of changing a liquid permeation rate through a semipermeable bodyof an osmotic delivery system to increase a delivery rate of abeneficial agent from the osmotic delivery system; a method of varying aliquid permeation rate through a semipermeable body of an osmoticdelivery system; an osmotic delivery system having a semipermeable bodyand a liquid impermeable sleeve; and an osmotic delivery system havingtwo abutting semipermeable bodies. Different liquid permeation ratesthrough semipermeable membranes of the osmotic delivery systemsaccording to embodiments of the present invention are obtainable byvarying the thickness and/or the surface area of the semipermeablemembrane that is immediately exposed to liquid when the osmotic deliverysystem is located in a liquid environment of use. Additionally,different desired liquid permeation rates through osmotic deliverysystem plugs according to embodiments of the present invention areobtainable from plugs formed from the same material having the samepermeability coefficient and uptake characteristics.

[0030] The foregoing and other objects may be obtained by an osmoticdelivery system plug that includes a semipermeable body. Thesemipermeable body has a recess having an interior surface beginning atan opening in the body and ending at a depth surface within thesemipermeable body, a liquid contact surface located opposite the depthsurface, and an outer surface located opposite the interior surface. Theouter surface includes means for sealing an environment of use from aninside of an enclosure of an osmotic delivery system in which the bodyis insertable. The body also has a predetermined plug thickness definedby the location of the depth surface relative to the fluid surface, anda predetermined wall width defined by the location of the outer surfacerelative to the interior surface. At least one of the predetermined plugthickness and predetermined wall width control a rate of liquidpermeation through the semipermeable body. The osmotic delivery systemplug also includes an insert located within the recess.

[0031] The foregoing and other objects may be obtained by an osmoticdelivery system plug that includes a semipermeable body at leastpartially positionable in an opening in an enclosure of an osmoticdelivery system. The semipermeable body includes a hollow interiorportion having a size selected to obtain a predetermined liquidpermeation rate through the semipermeable body. The liquid permeationrate controls a delivery rate of a beneficial agent from an osmoticdelivery system according to the present invention. The osmotic deliveryplug may also include an insert.

[0032] The foregoing and other objects and advantages may be obtained byan osmotic delivery system that includes an enclosure having an openingand a delivery port. The enclosure also has an interior holding a liquidswellable osmotic agent and a beneficial agent. The liquid swellableosmotic agent is for imbibing liquid from a surrounding environment andcausing a delivery rate of the beneficial agent from the enclosure. Theosmotic delivery system includes a plug having a semipermeable body atleast partially positioned in the opening. The semipermeable bodyincludes a hollow interior portion having a size selected to obtain apredetermined liquid permeation rate through the semipermeable body. Theliquid permeation rate is for controlling the delivery rate of thebeneficial agent from the osmotic delivery system.

[0033] The foregoing and other objects and advantages may be obtained bya method of controlling a delivery rate of a beneficial agent from theaforementioned osmotic drug delivery system using the aforementionedosmotic delivery system plug, the method including the steps of:determining a desired delivery rate of the beneficial agent; selecting aplug with a hollow interior portion sized to obtain a predeterminedliquid permeation rate through the semipermeable body corresponding tothe desired delivery rate of the beneficial agent; positioning the plugat least partially within the opening of the enclosure; and locating theosmotic drug delivery system in an environment of use.

[0034] The foregoing and other objects and advantages may be obtained bya method of changing a liquid permeation rate through a semipermeablebody of an osmotic delivery system to increase a delivery rate of abeneficial agent from the osmotic delivery system. The method includesthe steps of making a semipermeable body having a liquid permeabilitycoefficient and a thickness, and changing the thickness of thesemipermeable body to alter a liquid permeation rate through thesemipermeable body.

[0035] The foregoing and other objects and advantages may be obtained bya method of varying a liquid permeation rate through a semipermeablebody of an osmotic delivery system in which a liquid impermeable sleeveis mounted on the semipermeable body to vary a delivery rate of abeneficial agent from the osmotic delivery system. The method includesthe step of moving the liquid impermeable sleeve along an exteriorsurface of the semipermeable body to vary an amount of surface area ofthe exterior surface that is immediately exposed to liquids when theosmotic delivery system is located in a liquid environment of use.

[0036] The foregoing and other objects and advantages may be obtained bya method of varying a liquid permeation rate through a semipermeablebody of an osmotic delivery system to vary a delivery rate of abeneficial agent from the osmotic delivery system. The method includesthe step of selecting a desired liquid permeation rate through thesemipermeable body of the osmotic delivery system, and providing aplurality of semipermeable body elements in abutting relation to oneanother to define the semipermeable body and to achieve the selectedliquid permeation rate.

[0037] The foregoing and other objects and advantages may be obtained byan osmotic delivery system having a liquid impermeable enclosure havingan interior holding a beneficial agent and an osmotic agent for imbibingliquid from a surrounding environment and causing delivery of thebeneficial agent from the liquid impermeable enclosure. A semipermeablebody is in liquid communication with the liquid impermeable enclosurefor permitting liquid to permeate through the semipermeable body to theosmotic agent. A liquid impermeable sleeve separate from the liquidimpermeable enclosure and surrounding a portion of a surface of thesemipermeable body such that the portion of the surface is notimmediately exposed to liquid when the osmotic delivery system islocated in a liquid environment of use and such that the semipermeablebody includes an exposure surface defined by an area of the surface thatis not surrounded by the liquid impermeable sleeve and is immediatelyexposed to liquids when the osmotic delivery system is located in theliquid environment of use.

[0038] The foregoing and other objects and advantages may be obtained byan osmotic delivery system including an enclosure having an interiorholding a beneficial agent and an osmotic agent. The osmotic agent isfor imbibing liquid from a surrounding environment and causing deliveryof the beneficial agent from the enclosure. A first semipermeable bodyis in liquid communication with the enclosure for permitting liquid topermeate through the first semipermeable body to the osmotic agent. Asecond semipermeable body abuts the first semipermeable body and is inliquid communication with the first semipermeable body so as to permitliquid to permeate through the first semipermeable body and the secondsemipermeable body to the osmotic agent.

[0039] The foregoing and other objects and advantages may be obtained byan osmotic delivery system having an enclosure. The enclosure includesan opening, a delivery port, and an interior holding a liquid swellableosmotic agent and a beneficial agent. The liquid swellable osmotic agentis for imbibing liquid from a surrounding environment and causing adelivery rate of the beneficial agent from the enclosure. The osmoticdelivery system includes a plug having a semipermeable body. The plug isat least partially positioned in the opening. The semipermeable body hasan exposure surface that is immediately exposed to liquids when theosmotic delivery system is located in a liquid environment of use. Theexposure surface includes a conical surface.

BRIEF DESCRIPTION OF THE DRAWINGS

[0040] The invention will be described in greater detail with referenceto the accompanying drawings in which like elements bear like referencenumerals, and wherein:

[0041]FIG. 1 is a cross sectional view of a prior art osmotic drugdelivery device which incorporates a membrane plug.

[0042]FIG. 2 is a side view of an osmotic delivery system plug orosmotic delivery system semipermeable body assembly according to thepresent invention.

[0043]FIG. 3 is an end view of the osmotic delivery system plug of FIG.2.

[0044]FIG. 4A is a sectional view of a semipermeable body of the osmoticdelivery system plug according to the present invention taken along theline 4-4 of FIG. 3.

[0045]FIG. 4B is a sectional view of an osmotic delivery system plug,which includes an insert, according to the present invention taken alongthe line 4-4 of FIG. 3.

[0046]FIG. 5 is a side view of an insert of an osmotic delivery systemplug according to the present invention.

[0047]FIG. 6 is an end view of the insert of FIG. 5.

[0048]FIG. 7 is a sectional view of an osmotic delivery system accordingto the present invention.

[0049]FIG. 8 is a graph illustrating the increased release rate of anosmotic delivery system according to the present invention, whichutilizes an osmotic delivery system plug according to the presentinvention.

[0050]FIG. 9 is a graph illustrating the release rate of osmoticdelivery systems according to the present invention having osmoticdelivery system plugs according to the present invention; the plugs havedifferent depth recesses and are all made from a polyurethane materialwith 18% water uptake.

[0051]FIG. 10 is a graph illustrating the release rate of osmoticdelivery systems according to the present invention having osmoticdelivery system plugs according to the present invention; the plugs havedifferent depth recesses and are all made from a polyurethane materialwith 33% water uptake.

[0052]FIG. 11 is a graph illustrating the release rate of osmoticdelivery systems according to the present invention having osmoticdelivery system plugs according to the present invention; the plugs havedifferent depth recesses and are all made from a polyurethane materialwith 49% water uptake.

[0053]FIG. 12 is a side view of another osmotic delivery system plugaccording to the present invention.

[0054]FIG. 13 is a sectional view of another osmotic delivery systemaccording to the present invention having a semipermeable body andliquid impermeable sleeve, where both the semipermeable body and theliquid impermeable sleeve have been inserted in an opening of theenclosure of the osmotic delivery system.

[0055]FIG. 14 is a partial sectional view of another osmotic deliverysystem according to the present invention having a semipermeable bodyand liquid impermeable sleeve, where only the semipermeable body hasbeen inserted into the enclosure of the osmotic delivery system.

[0056]FIG. 15 is a partial sectional view of another osmotic deliverysystem according to the present invention having a semipermeable bodyand liquid impermeable sleeve, where the semipermeable body has beeninserted into the enclosure and the enclosure is received by the liquidimpermeable sleeve.

[0057]FIG. 16 is a partial sectional view of another osmotic deliverysystem according to the present invention having an enclosure with aplurality of grooves along which the enclosure and a semipermeable bodymay be cut.

[0058]FIG. 17 is a partial sectional view of another osmotic deliverysystem according to the present invention having a semipermeable bodyand liquid impermeable sleeve, where the liquid impermeable sleeve isthreaded on the enclosure of the osmotic delivery system and is moveablewith respect to the semipermeable body.

[0059]FIG. 18 is a sectional view of another osmotic delivery systemaccording to the present invention having a semipermeable body and aliquid impermeable sleeve, where the liquid impermeable sleeve isslidable with respect to the enclosure of the osmotic delivery system.

[0060]FIG. 19 is a partial sectional view of another osmotic deliverysystem according to the present invention having a semipermeable bodyand a liquid impermeable sleeve that is threaded on the semipermeablebody and moveable with respect to the semipermeable body.

[0061]FIG. 20 is an exploded sectional view of another osmotic deliverysystem according to the present invention having a plurality ofsemipermeable bodies that are stackable upon each other.

[0062]FIG. 21 is a side view of another osmotic delivery system plug orosmotic delivery system semipermeable body assembly according to thepresent invention.

[0063]FIG. 22 is an end view of the osmotic delivery system plug of FIG.21.

[0064]FIG. 23A is a sectional view of a semipermeable body of theosmotic delivery system plug according to the present invention takenalong the line 23-23 of FIG. 22.

[0065]FIG. 23B is a sectional view of another semipermeable body of theosmotic delivery system plug according to the present invention takenalong the line 23-23 of FIG. 22.

[0066]FIG. 24 is a side view of another insert of an osmotic deliverysystem plug according to the present invention.

[0067]FIG. 25 is a sectional view of an osmotic delivery systemaccording to the present invention having an osmotic delivery systemplug according to FIG. 21.

[0068]FIG. 26 is a perspective view of an osmotic delivery system plugaccording to the present invention, where the vertex of the cone-shapedplug has been tilted directly away from the viewer.

[0069]FIG. 27 is a perspective view of an osmotic delivery system plugaccording to the present invention, where the vertex of the cone-shapedplug has been tilted directly towards the viewer.

[0070]FIG. 28 is a sectional view of an osmotic delivery systemaccording to the present invention having an osmotic delivery systemplug according to FIG. 27.

[0071]FIG. 29 is a graph illustrating the theoretical increase insurface area of a semipermeable membrane body having a conical surfaceas compared with a semipermeable membrane body having a flat circularsurface, as the diameter of the membrane bodies correspondinglyincrease, where the thickness or height of the membrane bodies is equal.

[0072]FIG. 30 is a graph illustrating the theoretical increase in thebeneficial agent release rate of an osmotic delivery system, where theosmotic delivery system includes an osmotic delivery systemsemipermeable plug having a semipermeable body with a conical surfaceaccording to the present invention. FIG. 30 also illustrates the actualincrease in the beneficial agent release rate of an osmotic deliverysystem according to the present invention, where the osmotic deliverysystem includes an osmotic delivery system semipermeable plug having asemipermeable body with a circular surface according to the presentinvention.

DESCRIPTION OF THE PREFERRED EMBODIMENT

[0073] The present invention generally relates to osmotic deliverysystem semipermeable body assemblies for controlling a delivery rate ofa beneficial agent from osmotic delivery systems. FIGS. 7, 13-20, 25,and 28 each illustrate semipermeable body assemblies in cooperation withosmotic delivery systems according to the present invention.

[0074] FIGS. 2-6 illustrate features of an osmotic delivery system plugor semipermeable body assembly 30 according to one embodiment of thepresent invention. The osmotic delivery system plug 30 will be describedin reference to an exemplary osmotic delivery system 70 according to oneembodiment the present invention illustrated in FIG. 7. Theconfiguration of the osmotic delivery system plug 30 dictates the liquidpermeation rate through the plug, which generally controls the deliveryrate of a beneficial agent 72 from the osmotic delivery system 70.

[0075]FIG. 2 illustrates a side view of the osmotic delivery system plug30. The plug 30 is formed from a semipermeable body 32. Thesemipermeable body 32 is typically (but not necessarily) cylindricallyshaped, and has means for sealing or ribs 34 extending out from theouter surface 38 of the plug. The ribs 34 are the means by which theplug operates like a cork or stopper, obstructing and plugging anopening 79 in a capsule or enclosure 71 of the osmotic delivery system70 illustrated in FIG. 7. The means for sealing 34 may be the exemplaryribs, or may be other configurations such as threads, a tightinterference fit between an outer sealing surface of the plug body 32and the enclosure 71, glue, adhesives, ridges, lips, or other deviceswhich join the body 32 with the enclosure 71 to prevent leakage. Theplug body 32 is, therefore, intended for at least partial insertion intoan opening 79 of an enclosure 71, and the means for sealing 34 theenvironment of use from an inside of the enclosure 71 prevents liquidand other substances in the environment of use, besides the permeationliquid, from entering the osmotic delivery system 70 while alsopreventing materials from the inside of the delivery system from leakingor escaping to the environment of use.

[0076] As mentioned above, the osmotic delivery system plug 30 is madefrom a semipermeable body 32, which is formed from a semipermeablematerial. The semipermeable material of the body 32 allows liquids,especially water, to pass from an exterior environment of use into thecapsule or enclosure 71 to cause the osmotic agent 78 to swell. However,the semipermeable material forming the semipermeable body 32 is largelyimpermeable to the materials within the capsule and other ingredientswithin the fluid environment. Semipermeable compositions suitable forthe semipermeable body 32 are well known in the art, examples of whichare disclosed in U.S. Pat. No. 4,874,388, the entire disclosure of whichis incorporated herein by reference. Such possible semipermeablematerials from which the body 32 can be made include, but are notlimited to, for example, Hytrel polyester elastomers (DuPont), celluloseesters, cellulose ethers and cellulose ester-ethers, water flux enhancedethylene-vinyl acetate copolymers, semipermeable membranes made byblending a rigid polymer with water-soluble low molecular weightcompounds, and other semipermeable materials well known in the art. Theabove cellulosic polymers have a degree of substitution, D.S., on theanhydroglucose unit, from greater than 0 up to 3 inclusive. By, “degreeof substitution,” or “D.S.,” is meant the average number of hydroxylgroups originally present on the anhydroglucose unit comprising thecellulose polymer that are replaced by a substituting group.Representative materials include, but are not limited to, one selectedfrom the group consisting of cellulose acylate, cellulose diacetate,cellulose triacetate, mono-, di-, and tricellulose alkanylates, mono-,di-, and tricellulose aroylates, and the like. Exemplary cellulosicpolymers include cellulose acetate having a D.S. up to 1 and an acetylcontent up to 21%; cellulose acetate having a D.S. of 1 to 2 and anacetyl content of 21% to 35%; cellulose acetate having a D.S. of 2 to 3and an acetyl content of 35% to 44.8%, and the like. More specificcellulosic polymers include cellulose propionate having a D.S. of 1.8and a propionyl content of 39.2% to 45% and a hydroxyl content of 2.8%to 5.4%; cellulose acetate butyrate having a D.S. of 1.8 and an acetylcontent of 13% to 15% and a butyryl content of 34% to 39%; celluloseacetate butyrate having an acetyl content of 2% to 29%, a butyrylcontent of 17% to 53% and a hydroxyl content of 0.5% to 4.7%; celluloseacetate butyrate having a D. S. of 1.8, and acetyl content of 4% averageweight percent and a butyryl content of 51%; cellulose triacylateshaving a D.S. of 2.9 to 3 such as cellulose trivalerate, cellulosetrilaurate, cellulose tripalmitate, cellulose trisuccinate, andcellulose trioctanoate; cellulose diacylates having a D.S. of 2.2 to 2.6such as cellulose disuccinate, cellulose dipalmitate, cellulosedioctanoate, cellulose dipentate; coesters of cellulose such ascellulose acetate butyrate and cellulose, cellulose acetate propionate,and the like.

[0077] Other materials for the body 32 are polyurethane,polyetherblockamide (PEBAX, commercially available from ELF ATOCHEM,Inc.), injection-moldable thermoplastic polymers with somehydrophilicity such as ethylene vinyl alcohol (EVA). In general, thebody 32 is made from semipermeable materials having a water uptakeranging from 1% to 80%, preferably less than 60%, but more preferablyless than 50%. The composition of the semipermeable body 32 is permeableto the passage of external liquids such as water and biological liquids,and it is substantially impermeable to the passage of beneficial agents,osmopolymers, osmagents, and the like.

[0078] As illustrated in FIGS. 2 and 7, the outer surface 38 of thesemipermeable body 32 and the ribs 34 are meant for at least partialinsertion in an osmotic delivery system opening 79. The plug 30 isinsertable into the opening 79 until a stop surface 36 of the body 32abuts the wall of the enclosure 71. Because at least a portion of theplug 30 is within the enclosure, and has means for sealing 34, only aportion of the plug and body 32 is exposed to liquids in the environmentof use. In the embodiment of the present invention illustrated in FIGS.2-7, the liquid contact surface 48 is the portion of the semipermeablebody which is immediately exposed to liquids when the osmotic deliverysystem is placed in a liquid environment of use. Thus, as shown in FIG.7, the liquid contact surface 48 is external of the enclosure 71, andthe surface of the plug within the enclosure 71 is generally notimmediately exposed to liquid when the osmotic delivery system is placedin a liquid environment of use. As shown in FIG. 2, the liquid contactsurface 48 preferably has smoothed or curved corners which are moreacceptable for implantation than sharp edges. Likewise, the outerdiameter 40 of the liquid contact surface 48, measured about thelongitudinal center axis C, is approximately equal to that of theenclosure 71 of the osmotic delivery system such that the interfacebetween the enclosure and the liquid contact surface of the body 32 isvoid of abrupt edges, ridges, or sharp corners.

[0079] Alternatively, the plug need not have a stop surface 36, asillustrated by the alternative embodiment of a plug or semipermeablebody assembly 130 shown in FIG. 12. The foregoing and followingdiscussion of the benefits and functions of the plug 30 also apply tothe plug 130. Thus, the plug 130 is assigned corresponding referencenumbers as the plug 30, increased by 100. The plug 130 also includesmany additional features and inherent functions, as discussed below. Theplug 130 may be inserted entirely within an opening of an enclosure ofan osmotic delivery system because the plug does not include a stopsurface or head preventing complete insertion. When the plug 130 iscompletely inserted within the enclosure of an osmotic delivery system,the cylindrical flat surface or end surface 148 defines the liquidcontact surface of the plug because it is immediately exposed to liquidswhen such an osmotic delivery system is placed in a liquid environmentof use. The plug 130 may also be partially inserted into an opening ofan osmotic delivery system enclosure such that the liquid contactsurface includes more than just the end surface 148. The plug 130includes a semipermeable body 132 that receives an insert 160, similarto the insert 60 described below.

[0080]FIG. 4A depicts a cross section of the semipermeable body 32. Thesemipermeable body 32 includes a hollow interior portion or recess 52.In the embodiment of the present invention depicted in FIG. 4A, therecess 52 is cylindrically shaped. The recess 52 has a cylindrical andlongitudinal interior surface 54 which begins at an insert opening 55formed by the recess in the insert end 56 of the semipermeable body 32,and ends at a depth surface 50 within the body 32. Because of thegenerally cylindrical shape of the outer surface 38 of the semipermeablebody 32 and the cylindrical shape of the recess 52, the body is thimbleor cup-shaped such that a “bottom of the cup” has a predetermined plugthickness t illustrated in FIG. 4B and the wall 57 has a predeterminedwall width w, both further described below. In general, thesemipermeable body 32 is cup-shaped because it is hollow, i.e., thesemipermeable body 32 includes a cavity, gap, space, or concaveindentation that defines a hollow area within the semipermeable body.

[0081] As shown in FIG. 4A, the predetermined wall width w is defined bythe location of the outer surface 38 relative to the interior surface54, and the predetermined plug thickness t is defined by the location ofthe depth surface 50 relative to the liquid contact surface 48. Thus,the depth of the depth surface 50 within the semipermeable body 32, andthe distance the interior surface 54 is from the longitudinal centeraxis C (or diameter 46 of the recess 52) determine the size of thehollow interior portion or recess 52 in the interior of thesemipermeable body 32. Together, the predetermined wall width w and thepredetermined plug thickness t define an “effective thickness” L of thesemipermeable body. As described below, by varying the effectivethickness L of the semipermeable body, the liquid permeation ratethrough the body can be controlled; this is beneficial because, forexample, different desired liquid permeation rates through osmoticdelivery system plugs 30 according to the present invention areobtainable from plugs formed from the same material having the samepermeability coefficient and liquid uptake characteristics. This isfurther beneficial because biocompatibility and toxicity tests need onlybe performed on one semipermeable material.

[0082] Theoretically, the liquid permeation rate dV/dt through asemipermeable membrane sheet in an osmotic delivery system is equal tothe liquid permeability coefficient P for the membrane multiplied by thesurface area of the membrane A and the osmotic pressure difference Δπbetween the osmotic agent and the liquid on the other side of themembrane, divided by the thickness of the membrane sheet L.

dV/dt=P A Δπ/L

[0083] The beneficial agent delivery rate dMt/dt is theoretically equalto the liquid permeation rate dV/dt multiplied by the concentration C ofthe beneficial agent.

dMt/dt=dV/dt•C={P A Δπ/L}•C

[0084] If the surface area A of the membrane body is kept constant, thenfor a selected membrane material, osmotic agent, and beneficial agentconcentration, the liquid permeation rate dV/dt through the membrane andthe beneficial agent delivery rate dMt/dt are each theoreticallyinversely proportional to the thickness L of the membrane.

[0085] Thus, by varying the thickness L of a membrane sheet, forexample, the liquid permeation rate may be controlled. The presentinvention controls the liquid permeation rate dV/dt through the membraneplug 30 by varying the effective thickness L of the semipermeable plugbody 32, which corresponds to the theoretical thickness L of a typicalsheet membrane, for example. Thus, by varying the size of the recess orhollow interior portion 52, or, in other words, by varying thepredetermined plug thickness t and/or the predetermined wall width w,the effective thickness L of the semipermeable body 32 of the osmoticdelivery system plug 30 may also be varied. For instance, by increasingthe effective thickness L of the semipermeable body 32 of the plug 30,the liquid permeation rate dV/dt through the plug may be decreased.Although the plug thickness t primarily influences the liquid permeationrate through the membrane plug 30 (see FIGS. 8-11), the wall width walso affects the liquid permeation rate, but to a lesser extent than theplug thickness t. The influence of the wall width w on the liquidpermeation rate through the semipermeable membrane body 32 may be easilydetermined through experimentation.

[0086] In the above described manner, the liquid permeation rate dV/dtthrough the membrane plug 30 can be controlled. This is advantageousbecause low liquid uptake membrane materials can be used to fashionosmotic delivery system plugs 30 according to the present invention withfast liquid permeation rates. Such fast permeation rates were previouslyachieved by fashioning plugs out of high liquid uptake and possiblybiologically unstable membrane materials, which occasionally permititems in the interior of the osmotic delivery system to leak to theenvironment of use.

[0087] Osmotic delivery system plugs 30 according to the presentinvention permit the administration of beneficial agents 72 from osmoticdelivery systems at rapid delivery rates over a relatively short periodof time, even though the plugs may use a semipermeable material which,as measured against previous membrane plugs, has a low permeabilitycoefficient. These low permeability coefficient membrane materials donot have high liquid uptake characteristics, and do not swell asdramatically as high uptake materials when the liquid from thesurrounding environment permeates through the membrane. Thus, theosmotic delivery plug 30 that includes a hollow interior portion 52sized for a fast liquid permeation rate does not overly swell and creepout of the capsule, or permit the osmotic agent 78 to leak from thecapsule. Furthermore, the osmotic delivery plug 30 may be made frommaterials that are stable in biological environments, and do notsignificantly degrade over time, which could permit fluids, crystals, orpowder within the interior of the capsule 71 to leak to the environmentof use.

[0088] Because the present invention permits high liquid permeationrates to be obtained from plugs 30 made from generally low uptakematerials which can fit tightly into the osmotic delivery systemenclosure, the plug remains structurally rigid, and there is no need forglues or adhesives, typically necessary to keep high uptake and swellingmembrane plugs intact.

[0089] Another important benefit of controlling the effective thicknessL of the osmotic delivery system plug 30 is that different liquidpermeation rates are obtainable from the same semipermeable materialhaving a set permeability coefficient. A different membrane materialneed not be used for every system which has a different desiredbeneficial agent delivery rate, and biocompatibility and toxicity testsneed only be performed on one semipermeable material.

[0090] The hollow interior portion or recess 52 illustrated in FIGS. 4Aand 4B is cylindrical, having a recess diameter 46. By increasing therecess diameter 46, the predetermined wall width w decreases. Althoughthe cylindrical configuration of the recess 52 is preferred, otherconfiguration recesses fall within the confines of the presentinvention. For example, the recess or hollow interior portion 52 may besquare, rectangular, octagonal, triangular, oval, half circular, orcircular. Likewise, the hollow interior portion 52 may be a series orplurality of recesses, tubes, slots, or gaps within the interior of thesemipermeable body 32. All of the above, and other configurations, wouldfunction to control the effective thickness L of the semipermeable body32 as contemplated by the present invention.

[0091] The semipermeable body 32 is preferably injection molded.However, the semipermeable body may be fashioned by a different process.For example, the semipermeable body may also be made from extrusion,reaction injection molding, rotational molding, thermoforming,compression molding, and other known casting processes. Injectionmolding is preferable in that the ejector pin or core may be used toform the recess 52, and different length and sized ejector pins or coresmay be easily changed to fashion different sized recesses tocontrollably vary the liquid permeation rate through the membrane body32 of the plug 30. Additionally, the recess 52 may be formed in thesemipermeable body 32 after the semipermeable body has been formedwithout a recess. For example, a cylinder of semipermeable material maybe fabricated and sliced into smaller cylinders. Thereafter, acylindrical section may be removed from the semipermeable body to formthe recess 52 in the body. Thus, the liquid permeation rate through thesemipermeable body 32 may be changed by first making a semipermeablebody having a liquid permeability coefficient and a thickness, and thenchanging the thickness of the semipermeable body to alter the liquidpermeation rate through the semipermeable body.

[0092] In one embodiment of the present invention, the semipermeablebody 32 was formed by injection molding. The semipermeable material usedin the injection molding process was TECOPHILIC HP60D-20. The followinginjection molding operating parameters were used to form the abovedescribed semipermeable body. NOZZLE TEMP. ZONE 1 183° C. INJ. TIME 4SEC. BARREL TEMP. ZONE 2 180° C. HOLD TIME 2 SEC. BARREL TEMP. ZONE 3175° C. CLAMP CLOSED 20 SEC. BARREL TEMP. ZONE 4 170° C. TIME HOLDINGPRESSURE 500 PSI SCREW SPEED 430 RPM INJECTION PRESSURE 500 PSI BACKPRESSURE 200 PSI

[0093]FIGS. 5 and 6 illustrate an insert 60 which is included in anexemplary osmotic delivery plug 30 or osmotic delivery systemsemipermeable body assembly in accordance with the present invention. Asshown in FIG. 4B, the insert 60 is intended for insertion into thecylindrical recess or hollow interior portion 52. In the embodiment ofthe present invention illustrated in FIGS. 5 and 6, the insert iscylindrically shaped to match the shape of the hollow interior portion52. Thus configured, the insert 60 has a cylindrical peripheral surface66, a flat top surface 62, and flat contact surface 64 located oppositethe top surface. The insert 60 is sized such that the hollow interiorportion 52 matingly receives the insert. In instances where theeffective thickness L of the membrane body 32 is decreased by increasingthe recess diameter 46 of the hollow interior portion 52, the diameterof the insert 60 is also increased to substantially match the increasedrecess diameter 46. Likewise, the longitudinal length of the insert 60depicted in FIGS. 5 and 6 is substantially equal to the depth of therecess 52 within the semipermeable body 32.

[0094] It will be appreciated that the insert 60 may be in any number ofdifferent shapes and sizes, but preferably matches the shape and size ofthe hollow interior portion 52 into which the insert 60 is inserted.

[0095] The insert 60 is preferably inserted in the recess 52 forassisting the semipermeable body 32 in effecting a seal with theinterior of the enclosure 71. Because the semipermeable body 32 istypically flexible and resilient, the wall 57 may flex toward theinterior of the recess 52 after the plug 30 is inserted into theenclosure 71. By inserting the preferably rigid insert 60 into theinsert opening 55 of the recess 52 such that the insert is matinglyreceived, the wall 57 will not flex inwardly toward the insert and theseal formed by the outer surface 38 and the ribs 34 is maintained.

[0096] It is also preferable that the insert 60 be substantiallypervious to liquids, permitting the liquid which has permeated throughthe semipermeable body 32 to freely travel though the insert to theosmotic agent 78 of the osmotic delivery system 70. It is preferablethat the insert 60 be more pervious to liquids than the semipermeablemembrane body 32 such that the liquid permeation rate through thesemipermeable body 32 with the insert 60 therein is not substantiallyaffected by the liquid permeability of the insert. In other words, theliquid permeation rate through the semipermeable body 32 should notchange significantly because the insert 60 has been inserted into therecess 52. Because the insert 60 is preferably more pervious to liquidsthan the semipermeable body 32, the insert 60 will not adversely affectthe liquid permeation rate through the semipermeable body 32 to anysignificant degree. Materials from which the insert 60 may be fashioninclude, but are not limited to, metals, glasses, and plastics which arefashioned with pores, holes or liquid channels. Preferred materials forthe insert 60 are fritted glass or metal, and macroporous polymers.

[0097] Because the insert 60 according to the present inventionmaintains the seal of the semipermeable body 32 with the enclosure 71,there is no need for glues or adhesives to effect a seal.

[0098] Alternatively, the insert 60 may not be inserted into the recess52. Although the insert 60 is preferred because it maintains the seal,instances may arise where the insert 60 is not necessary. For example,if the semipermeable body 32, according to an alternative embodiment ofthe present invention not depicted, has a hollow interior portion 52with a small recess diameter 46 and predetermined depth, the insert 60may not be needed to assist in effecting the seal. Generally, thepredetermined wall thickness w and the structural characteristics of thesemipermeable body 32 determine whether of not a rigid insert is neededto assist in effecting the seal, which is determinable by experimentalmethods well known in the art.

[0099] The insert 60 may also be impervious to liquids or partiallyimpervious to some liquids such that the liquid permeation rate throughthe osmotic delivery system plug 30 is altered by the insert materialand its configuration. For example, the insert may be fashioned from asemipermeable material having a different permeability coefficient thanthat of the semipermeable body 32.

[0100] The insert 60 may also function as an osmotic agent. For example,the insert may be fashioned from polymers blended with 60% sodiumchloride or salt embedded in a rigid structure. In such an embodiment,the sodium chloride will function as an “initial” osmotic engine,helping initiate the flow of beneficial agent from the osmotic deliverysystem 70 upon insertion into a liquid environment of use. After thesodium chloride has lost its osmotic abilities and/or has dissolvedaway, the polymer (having pores, for example) remains in the recess 52and assists in making the seal and/or also partially controlling thepermeation rate of liquid into the enclosure 71.

[0101]FIG. 7 illustrates an example of an osmotic delivery device orsystem 70 according to the present invention. The configurationillustrated in FIG. 7 is one example of an osmotic delivery device andis not to be construed as limiting the present invention. The presentinvention is generally applicable to all osmotic delivery devices havingany number of shapes, and to all such devices administered in anyvariety of methods such as oral, ruminal, and implantable osmoticdelivery techniques. Such devices may also be placed in reservoirs,tanks, or pools.

[0102] The osmotic drug delivery device 70, as illustrated in FIG. 7,includes an elongated substantially cylindrical enclosure 71 having anopening 79 which, as illustrated in FIG. 7, is plugged with the plug 30.The end of the enclosure opposite the opening 79 has one or moredelivery ports 75 for delivering a beneficial agent 72 from the osmoticdelivery system 70. The elongated enclosure 71 is formed of a materialwhich is sufficiently rigid to withstand expansion of an osmotic agent78 without changing size or shape. The enclosure 71 is preferablysubstantially impermeable to fluids in the environment as well as toingredients contained within the osmotic delivery device such that themigration of such materials into or out of the device through theimpermeable material of the enclosure is so low as to have substantiallyno adverse impact on the function of the osmotic delivery device.

[0103] Within the enclosure 71 is a beneficial agent 72 to be delivered.Such a beneficial agent 72 may optionally include pharmaceuticallyacceptable carriers and/or additional ingredients such as antioxidants,stabilizing agents, permeation enhancers, etc.

[0104] The embodiment of the present invention illustrated in FIG. 7includes an optional movable piston 74. The osmotic agent 78 within theenclosure 71 is separated from the beneficial agent 72 by the movablepiston 74. The enclosure 71 receives the osmotic agent 78, which in theembodiment of the present invention depicted in FIG. 7 is one or moreosmotic tablets. Osmotic agents, specifically the osmotic tablet 78 ofthe embodiment of the present invention illustrated FIG. 7, drive theosmotic flow of osmotic delivery devices. However, the osmotic agent 78need not be a tablet; it may be other conceivable shapes, textures,densities, and consistencies and still be within the confines of thepresent invention.

[0105] When used, the movable separating member or piston 74 is asubstantially cylindrically member which is configured to fit within theenclosure 71 in a sealed manner which allows the piston to slide along alongitudinal direction within the enclosure. The piston 74 preferably isformed of an impermeable resilient material and includes annular ringshape protrusions 76 which form a moveable or sliding seal with theinner surface of the enclosure.

[0106] As illustrated in FIG. 7, the osmotic delivery device 70 includesthe above described osmotic delivery system plug 30, which is insertedin the opening 79 of the enclosure 71 after placing the osmotic agent 78within the enclosure. The plug 30 allows liquid to pass from anenvironment of use into the enclosure 71 to cause the osmotic agent 78to swell. However, as described above, the material forming thesemipermeable body 32 is largely impermeable to the materials within theenclosure and other ingredients within the environment of use.

[0107] Materials which may be used for the enclosure 71 must besufficiently strong to ensure that the enclosure will not leak, crack,break, or distort under stresses to which it would be subjected duringimplantation or under stresses due to the pressures generated duringoperation. Because the osmotic delivery system plug 30 enables rapidliquid permeation rates to be obtained from a semipermeable body 32 madefrom a low uptake membrane material, the risk that the enclosure 71 mayrupture or crack from pressures generated by high uptake and highswelling membrane plugs is reduced.

[0108] The enclosure 71 may be formed of chemically inert andbiocompatible, natural or synthetic materials which are known in theart. The enclosure material is preferably a non-bioerodible materialwhich may remain in the patient after use, such as titanium or atitanium alloy, and is largely impermeable to materials within andoutside the enclosure. However, the material of the enclosure mayalternatively be a bioerodible material which bioerodes in theenvironment after dispensing the beneficial agent. Generally, preferredmaterials for the enclosure 71 are those acceptable for human implants.

[0109] In general, typical materials of construction suitable for theenclosure 71 according to the present invention include non-reactivepolymers or biocompatible metals or alloys. The polymers includeacrylonitrile polymers such as acrylonitrile-butadiene-styreneterpolymer, and the like; halogenated polymers such aspolytetrafluoroethylene, polychlorotrifluoroethylene, copolymertetrafluoroethylene and hexafluoropropylene; polyimide; polysulfone;polycarbonate; polyethylene; polypropylene; polyvinylchloride-acryliccopolymer; polycarbonate-acrylonitrile-butadiene-styrene; polystyrene;and the like. Metallic materials useful for the enclosure 71 includestainless steel, titanium, platinum, tantalum, gold, and their alloys,as well as gold-plated ferrous alloys, platinum-plated ferrous alloys,cobalt-chromium alloys and titanium nitride coated stainless steel.

[0110] In general, materials suitable for use in the movable separatingmember 74 are elastomeric materials including the non-reactive polymerslisted above, as well as elastomers in general, such as polyurethanesand polyamides, chlorinated rubbers, styrene-butadiene rubbers, andchloroprene rubbers.

[0111] The osmotic agent, illustrated in FIG. 7 by the osmotic tablet78, is a liquid-attracting agent used to drive the flow of thebeneficial agent. The osmotic agent may be an osmagent, an osmopolymer,or a mixture of the two. Species which fall within the category ofosmagent, i.e., the non-volatile species which are soluble in water andcreate the osmotic gradient driving the osmotic inflow of water, varywidely. Examples are well known in the art and include magnesiumsulfate, magnesium chloride, potassium sulfate, sodium chloride, sodiumsulfate, lithium sulfate, sodium phosphate, potassium phosphate,d-mannitol, sorbitol, inositol, urea, magnesium succinate, tartaricacid, raffinose, and various monosaccharides, oligosaccharides andpolysaccharides such as sucrose, glucose, lactose, fructose, anddextran, as well as mixtures of any of these various species.

[0112] Species which fall within the category of osmopolymer arehydrophilic polymers that swell upon contact with water, and these varywidely as well. Osmopolymers may be of plant or animal origin, orsynthetic, and examples of osmopolymers are well known in the art.Examples include: poly(hydroxy-alkyl methacrylates) with molecularweight of 30,000 to 5,000,000, poly(vinylpyrrolidone) with molecularweight of 10,000 to 360,000, anionic and cationic hydrogels,polyelectrolyte complexes, poly(vinyl alcohol) having low acetateresidual, optionally cross-linked with glyoxal, formaldehyde orglutaraldehyde and having a degree of polymerization of 200 to 30,000, amixture of methyl cellulose, cross linked agar andcarboxymethylcellulose, a mixture of hydroxypropl methycellulose andsodium carboxymethylcellulose, polymers of N-vinyllactams,polyoxyethylene-polyoxypropylene gels, polyoxybutylene-polyethyleneblock copolymer gels, carob gum, polyacrylic gels, polyester gels,polyurea gels, polyether gels, polyamide gels, polypeptide gels,polyamino acid gels, polycellulosic gels, carbopol acidic carboxypolymers having molecular weights of 250,000 to 4,000,000, Cyanamerpolyacrylamides, cross-linked indene-maleic anhydride polymers,Good-Rite polyacrylic acids having molecular weights of 80,000 to200,000, Polyox Polyethylene oxide polymers having molecular weights of100,000 to 5,000,000, starch graft copolymers, and Aqua-Keeps acrylatepolymer polysaccharides.

[0113] The osmotic agent 78 may be manufactured by a variety oftechniques, many of which are known in the art. In one such technique,an osmotically active agent 78 is prepared as solid or semi-solidformulations and pressed into pellets or tablets whose dimensionscorrespond to slightly less than the internal dimensions of therespective chambers which they will occupy in the enclosure interior.Depending on the nature of the materials used, the agent and other solidingredients which may be included may be processed prior to theformation of the pellets by such procedures as ballmilling, calendaring,stirring or rollmilling to achieve a fine particle size and hence fairlyuniform mixtures of each. The enclosure 71 may be formed from any of thewall-forming materials disclosed above by the use of a mold, with thematerials applied either over the mold or inside the mold, depending onthe mold configuration. Any of the wide variety of techniques known inthe pharmaceutical industry may be used to form the enclosure 71.

[0114] In assembling the osmotic delivery device 70 according to oneembodiment of the present invention, the piston 74 is first insertedinto the enclosure 71. Once the osmotic agent pellets or tablets 78 havebeen formed, they are placed inside the pre-formed enclosure 71 on topof the separating member 74. Then the osmotic delivery system plug 30,according to one embodiment of the present invention, is placed into theopening 79 of the enclosure 71 to close off and seal one end of theosmotic delivery system.

[0115] The delivery port 75 is an orifice formed by conventionaltechniques which are known in the art. Included among these methods aremechanical drilling, laser drilling, and molding. The enclosure willcontain at least one such delivery port 75, and in most configurations,one delivery port will suffice. However, two or more delivery ports 75may be present without departing from the present invention. Thedelivery port 75 may also be formed in a separate plug-like device andthen inserted into a second opening (not illustrated) of the enclosure71 opposite the first opening 79. The dimensions of the port 75 in termsof both diameter and length will vary with the type of beneficial agent72, the rate at which the beneficial agent is to be delivered, and theenvironment into which it is to be delivered. The considerationsinvolved in determining the optimum dimensions of the delivery port 75for any particular enclosure or beneficial agent 72 are the same asthose for delivery ports or orifices of enclosures of the prior art, andselection of the appropriate dimensions will be readily apparent tothose skilled in the art.

[0116] In other embodiments of this invention, the beneficial agent 72contained in the enclosure 71 may include flowable compositions such asliquids, suspension, or slurries, which are typically poured into theenclosure after the osmotic agent 78 and the piston 74 have beeninserted.

[0117] Animals to whom beneficial agents may be administered usingsystems of this invention include humans and other animals. Theinvention is of particular interest for application to humans andhousehold, sport, and farm animals, particularly mammals. For theadministration of beneficial agents to animals, the devices of thepresent invention may be implanted subcutaneously or intraperitoneallywherein aqueous body fluids or liquids are available to activate theosmotic agent. Devices of the invention may also be administered to therumen of ruminant animals, in which embodiment the devices may furthercomprise a density element for maintaining the device in the rumen forextended periods of time of up to 120 days or longer. Density elementsare well known in the art of drug delivery devices.

[0118] The present invention applies to the administration of beneficialagents in general, which include any physiologically orpharmacologically active substance. The beneficial agent 72 may be anyof the agents which are known to be delivered to the body of a human oran animal such as medicaments, vitamins, nutrients, or the like. Thebeneficial agent 72 may also be an agent which is delivered to othertypes of aqueous environments such as pools, tanks, reservoirs, and thelike. Included among the types of agents which meet this description arebiocides, sterilization agents, nutrients, vitamins, food supplements,sex sterilants, fertility inhibitors and fertility promoters.

[0119] Drug agents which may be delivered by the present inventioninclude drugs which act on the peripheral nerves, adrenergic receptors,cholinergic receptors, the skeletal muscles, the cardiovascular system,smooth muscles, the blood circulatory system, synoptic sites,neuroeffector junctional sites, endocrine and hormone systems, theimmunological system, the reproductive system, the skeletal system,autacoid systems, the alimentary and excretory systems, the histaminesystem and the central nervous system. Suitable agents may be selectedfrom, for example, proteins, enzymes, hormones, polynucleotides,nucleoproteins, polysaccharides, glycoproteins, lipoproteins,polypeptides, steroids, analgesics, local anesthetics, antibioticagents, anti-inflammatory corticosteroids, ocular drugs and syntheticanalogs of these species.

[0120] Examples of drugs which may be delivered by devices according tothis invention include, but are not limited to prochlorperzineedisylate, ferrous sulfate, aminocaproic acid, mecamylaminehydrochloride, procainamide hydrochloride, amphetamine sulfate,methamphetamine hydrochloride, benzamphetamine hydrochloride,isoproterenol sulfate, phenmetrazine hydrochloride, bethanecholchloride, methacholine chloride, pilocarpine hydrochloride, atropinesulfate, scopolamine bromide, isopropamide iodide, tridihexethylchloride, phenformin hydrochloride, methylphenidate hydrochloride,theophylline cholinate, cephalexin hydrochloride, diphenidol, meclizinehydrochloride, prochlorperazine maleate, phenoxybenzamine,thiethylperzine maleate, anisindone, diphenadione erythrityltetranitrate, digoxin, isoflurophate, acetazolamide, methazolamide,bendroflumethiazide, chloropromaide, tolazamide, chlormadinone acetate,phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetylsulfisoxazole, erythromycin, hydrocortisone, hydrocorticosteroneacetate, cortisone acetate, dexamethasone and its derivatives such asbetamethasone, triamcinolone, methyltestosterone, 17-S-estradiol,ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone,17-α-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel,norethindrone, norethisterone, norethiederone, progesterone,norgesterone, norethynodrel, aspirin, indomethacin, naproxen,fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate,propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine,imipramine, levodopa, chlorpromazine, methyldopa,dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen,ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrouslactate, vincamine, diazepam, phenoxybenzamine, diltiazem, milrinone,capropril, mandol, quanbenz, hydrochlorothiazide, ranitidine,flurbiprofen, fenufen, fluprofen, tolmetin, alclofenac, mefenamic,flufenamic, difuinal, nimodipine, nitrendipine, nisoldipine,nicardipine, felodipine, lidoflazine, tiapamil, gallopamil, amlodipine,mioflazine, lisinolpril, enalapril, enalaprilat, captopril, ramipril,famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil,chlordiazepoxide, diazepam, amitriptyline, and imipramine. Furtherexamples are proteins and peptides which include, but are not limitedto, insulin, colchicine, glucagon, thyroid stimulating hormone,parathyroid and pituitary hormones, calcitonin, renin, prolactin,corticotrophin, thyrotropic hormone, follicle stimulating hormone,chorionic gonadotropin, gonadotropin releasing hormone, bovinesomatotropin, porcine somatotropin, oxytocin, vasopressin, GRF,prolactin, somatostatin, lypressin, pancreozymin, luteinizing hormone,LHRH, LHRH agonists and antagonists, leuprolide, interferons,interleukins, growth hormones such as human growth hormone, bovinegrowth hormone and porcine growth hormone, fertility inhibitors such asthe prostaglandins, fertility promoters, growth factors, coagultionfactors, human pancreas hormone releasing factor, analogs andderivatives of these compounds, and pharmaceutically acceptable salts ofthese compounds, or their analogs or derivatives.

[0121] The beneficial agent can be present in this invention in a widevariety of chemical and physical forms, such as solids, liquids andslurries. On the molecular level, the various forms may includeuncharged molecules, molecular complexes, and pharmaceuticallyacceptable acid addition and base addition salts such as hydrochlorides,hydrobromides, acetate, sulfate, laurylate, oleate, and salicylate. Foracidic compounds, salts of metals, amines or organic cations may beused. Derivatives such as esters, ethers and amides can also be used. Abeneficial agent can be used alone or mixed with other agents.

[0122] According to other embodiments of the present invention, theenclosure 71 may take different forms. For example, as described above,the delivery orifice 75 may be formed in a soft impermeable materialinserted into the enclosure 71. In addition, the moveable separatingmember 74 may be a flexible member such as a diaphragm, partition, pad,flat sheet, spheroid, or rigid metal alloy, and may be made of anynumber of inert materials. Furthermore, the osmotic device 70 mayfunction without the separating member 74, having simply an interfacebetween the osmotic agent 78 and the beneficial agent 72.

[0123] The devices of this invention are also useful in environmentsoutside of physiological or aqueous environments. For example, thedevices may be used in intravenous systems (attached to an IV pump orbag or to an IV bottle, for example) for delivering beneficial agents toan animal, primarily to humans. They may also be utilized in bloodoxygenators, kidney dialysis and electrophoresis, for example.Additionally, devices of the present invention may be used in thebiotechnology area, such as to deliver nutrients or growth regulatingcompounds to cell cultures. In such instances, activating mechanismssuch as mechanical mechanisms are particularly useful.

[0124]FIG. 8 is a graph of the release rate of beneficial agent overtime and compares an osmotic delivery system according to the presentinvention with an osmotic delivery system incorporating a conventionalmembrane plug, such as that illustrated in FIG. 1. As described above,the osmotic delivery system 70 according to the present inventionincludes an osmotic delivery system plug 30 according to the presentinvention. Both the prior membrane plug and the osmotic delivery systemplug 30 tested in FIG. 8 were made of the same membrane material, PEBAX.The chemical structure of PEBAX is:

[0125] n=5, or 11

[0126] m=2, or 4

[0127] x and y are selected according to the desired molecular weight.

[0128] As shown in FIG. 8, the osmotic delivery system 70 incorporatingthe prior membrane plug delivered approximately 2 μl/day of thebeneficial agent from the osmotic delivery system. Comparatively, theosmotic delivery system having a membrane plug 30 according to thepresent invention released about 4 μl/day of beneficial agent eventhrough the same semipermeable material was used for the plugs in eachosmotic delivery system tested.

[0129] FIGS. 9-11 are also graphs of the release rate of beneficialagent over time and each compare osmotic delivery systems according tothe present invention having membrane plugs 30 with various depthrecesses 52.

[0130] The objectives of the experiments conducted to obtain the resultsdepicted in FIGS. 9-11 were to evaluate (1) the influence of the depthof the interior portion 52 of the membrane plug 30 on the release rateof beneficial agent, and (2) the influence of the water uptake ofmembrane plug materials on the release rate. The subassembly componentsof the osmotic delivery systems 70 tested included: titanium enclosures71; 80% sodium chloride osmotic agent tablets 78 (2×50 mg); C-flexpistons 74; silicone medical fluid (350 cs); and HDPE spiral orificedelivery ports (6 mil channel diameter). Spiral orifice delivery portsare disclosed in U.S. patent Ser. No. 08/595,761, the entire disclosureof which is incorporated herein by reference.

[0131] The vehicle formulations of the beneficial agent used in theosmotic delivery systems tested was 2% Blue #1 in purified water (USP).The configuration of the membrane plugs 30 were: HP-60D-20b (1.5%clearance) with recess depths of 0, 59, 94 and 133 mils; HP-60D-42 (7.5%clearance) with recess depths of 0, 59, 94 and 133 mils; and HP-60D-60(7.5% clearance) with recess depths of 0, 59, 94 and 133 mils. Theinserts 60 tested in the membrane plugs 30 were made from HDPE porousrod with a pore size of 15-45 μg (available from POREX).

[0132] All pistons and enclosures were pre-lubricated. Sequentially,pistons 74 were first inserted into the enclosures 71. The enclosureswere then filled with 10 μl of PEG-400 and thereafter two osmotictablets 78 were inserted. The HDPE insert 30 was presoaked in PEG-400 toeliminate any air trapped in the pores. The semipermeable bodies 32 wereultradried and the porous HDPE inserts were pre-inserted into the recess52. After the osmotic delivery systems were assembled, they were thensubmerged in a water bath at 37° C. Beneficial agent release ratemeasurements were determined three times during the first week afterinsertion, two times during the second week, and weekly thereafter. Thedepth of the recess 52 and corresponding length of the insert 60 wereeither 0, 59, 94, or 131 mils, as measured from the insert ends 56 ofthe membrane plugs 30. The diameter of the inserts 60 and recesses 52for all tests were kept constant and were approximately 2.0 mm. Thediameter and thickness or length (measured from end to end) of thesemipermeable bodies 32 were also kept constant and were approximately2.99 mm (diameter) and 150 mils (length). The specific membrane materialused in the experiments was tecophilic polyurethane (TECOPHILIC,commercially available from THERMEDICS) having either 18%, 33% or 49%water uptake. The chemical structure of tecophilic polyurethane isunderstood to be:

[0133] Where the values of x and y depend on the monomer composition ofthe polymer and determine the water uptake value, the values of a and bdepend on the monomer distribution of the polymer, m=20-25, and n=12-17.

[0134] The test results are summarized below in Table 1. TABLE I Summaryof beneficial agent release rate tests for osmotic delivery system plugshaving different depth recesses. Water uptake Thickness t Depth ofhollow Release rate Duration Membrane (%) (mil) (mil) (ul/day) (days)Teco72b (#18709) 18 151   0 0.205 700 Teco72b (#20536) 18 92 59 0.298490 Teco72b (#19305) 18 57 94 0.468 310 Teco72b (#20535) 18 20 131 1.218 120 Teco77 (#18710) 33 151   0 1.322 110 Teco77 (#20509) 33 92 592.226  65 Teco77 (#20452) 33 57 94 5.086  29 Teco77 (#20508) 33 20 131 18.138   8 Teco73 (#18710) 49 151   0 3.188  46 Teco73 (#20509) 49 92 595.897  25 Teco73 (#20452) 49 57 94 12.568   12 Teco73 (#20508) 49 20131  16.121   9

[0135] The test results are illustrated in FIGS. 9-11. As describedabove, FIGS. 9-11 illustrate the release rate over time for osmoticdelivery systems including TECOPHILIC membrane plugs 30 having constantwater uptake and different depth recesses 52. As illustrated, byincreasing the depth of recess 52 (controlling the effective thickness Lof the membrane plugs), the release rate of the beneficial agentincreases. Thus, the liquid permeation rate through the membrane plugs30 according to the present invention may be controlled even though thepermeability coefficient for the membrane material is constant. In sum,many different membrane plugs 30 (having different effective thicknessesL and different permeation rates) may be formed from one membranematerial. This is especially advantageous in that delivery system plugsaccording to the present invention may be manufactured from onesemipermeable material which has been tested and shown to bebiocompatible does, not have high uptake characteristics, does not tendto dislodge from the delivery system enclosure, and does not permititems within the osmotic delivery system to escape or leak to theenvironment of use.

[0136] FIGS. 13-20, 25, and 28 illustrate alternative embodiments ofosmotic delivery systems according to the present invention. Theforegoing and following discussion of the benefits and functions of theosmotic delivery system 70 also applies to the osmotic delivery systems270, 370, 470, 570, 670, 770, 870, 970, 1070, and 2070. Thus, theosmotic delivery system illustrated in FIGS. 13-20, and 25 have beenassigned corresponding reference numbers as the osmotic delivery system70, increased by hundreds. The osmotic delivery systems illustrated inFIGS. 13-20, 25, and 28 also include many additional features andinherent functions, as described further below.

[0137]FIG. 13 illustrates one embodiment of an osmotic delivery deviceor system 270. As illustrated in FIG. 13, the osmotic delivery system270 includes an elongated substantially cylindrical enclosure 271 havingan opening through which a semipermeable body assembly 230 has beeninserted. The semipermeable body assembly 230 includes a semipermeablebody 232 and a liquid impermeable sleeve 280. The end of the enclosure271 opposite the opening through which the semipermeable body assembly230 has been inserted has one or more delivery ports 275 for deliveringa beneficial agent 272 from the osmotic delivery system 270. Theelongated enclosure 271 is formed of a material which is sufficientlyrigid to withstand expansion of an osmotic agent 278 without changingshape or size. The elongated enclosure 271 is preferably substantiallyimpermeable to fluids in the environment of use as well as toingredients contained within the osmotic delivery device 270 such thatthe migration of such materials into or out of the device through theimpermeable material of the enclosure is so low as to have substantiallyno adverse impact on the function of the osmotic delivery device.

[0138] Within the enclosure 271 is the beneficial agent 272 to bedelivered, and an optional piston 274. The osmotic agent 278 within theenclosure 271 is separated from the beneficial agent 272 by the piston274. The enclosure 271 receives the osmotic agent 278, which in theembodiment of the present invention depicted in FIG. 13 is one or moreosmotic tablets. The osmotic tablet 278 drives the osmotic flow of theosmotic delivery device 270.

[0139] As illustrated in FIG. 13, the osmotic delivery device 270includes an osmotic delivery system semipermeable body assembly 230having the semipermeable body 232 and the liquid impermeable sleeve 280which have been inserted into the cylindrical opening of the enclosure271. The osmotic agent 278 is directly adjacent to or touching thesemipermeable body 232. The semipermeable body 232 allows liquid to passfrom an environment of use into the enclosure 271 to cause the osmoticagent 278 to swell. However, as described earlier, the material formingthe semipermeable body 232 is largely impermeable to the materialswithin the enclosure and other ingredients within the environment ofuse. The semipermeable body 232 and the liquid impermeable sleeve 280together define the osmotic delivery system semipermeable body assembly230 that controls the delivery rate of the beneficial agent 272 from theosmotic delivery system 270. The configuration of the semipermeable body232 and the liquid impermeable sleeve 280 dictates the liquid permeationrate through the semipermeable body 252, which generally controls thedelivery rate of the beneficial agent 272 from the osmotic deliverysystem 270.

[0140] The semipermeable body 232 is cylindrically shaped, and the outeror exterior cylindrical surface 238 of the semipermeable body 232touches or contacts the sleeve 280. The liquid impermeable sleeve 280 istubular or barrel shaped, although it may be shaped otherwise and stillbe within the confines of the present invention. For example, the liquidimpermeable sleeve 280 may be thimble-shaped, V-shaped, or C-shaped. Theinterior cylindrical surface of the liquid impermeable sleeve 280 abutsagainst the exterior cylindrical surface 238 of the semipermeable body232. Thus, the liquid impermeable sleeve 280 forms a cylindrical tubesurrounding the semipermeable body 232. In the embodiment of the presentinvention illustrated in FIG. 13, the liquid impermeable sleeve 280 isthe same length as the semipermeable body 232 in the longitudinaldirection of the semipermeable body, and the entire cylindrical exteriorsurface 238 of the semipermeable body abuts against the entire interiorsurface of the sleeve 280.

[0141] The liquid impermeable sleeve 280 is of the same material or afunctionally similar material as that of the enclosure 271. The liquidimpermeable sleeve 280 is formed from a material that is largelyimpermeable to the materials within the enclosure 271 and otheringredients within the environment of use. More specifically, the liquidimpermeable sleeve 280 is preferably substantially impermeable to liquidin the environment of use as well as to ingredients contained with theosmotic delivery system 270 such that the migration of such materialsinto or out of the osmotic delivery system through the impermeablematerial of the liquid impermeable sleeve is so low as to havesubstantially no adverse impact on the function of the osmotic deliverydevice.

[0142] The liquid impermeable sleeve 280 and semipermeable body 232 areinsertable into an opening of the osmotic delivery system enclosure 271.The exterior surface of the portion of the liquid impermeable sleeve 280located within the enclosure 271 forms a seal with the interior surfaceof the enclosure 271. The portion of the exterior surface of the liquidimpermeable sleeve 280 located within the enclosure 271 seals theinterior of the enclosure 271 from the exterior environment. The sealmay be enhanced by ribs on the exterior outer surface of the liquidimpermeable sleeve 280 or the inner surface of the enclosure 271. Thus,the semipermeable body 232 and liquid impermeable sleeve 280, wheninserted into the enclosure 271, together operate like a cork orstopper, obstructing and plugging the opening in the enclosure 271 ofthe osmotic delivery system 270. FIG. 13 illustrates the semipermeablebody assembly 230 plugging the opening in the enclosure 271 of theosmotic delivery system 270.

[0143] The liquid impermeable sleeve 280 or the enclosure 271 mayinclude other means to effect a seal between the liquid impermeablesleeve 280 and the enclosure 271, such as threads, a tight interferencefit, grooves, ridges, lips, or other configurations which matingly jointhe liquid impermeable sleeve 280 with the enclosure 271 to preventleakage. Additionally, an adhesive may be used to bond the liquidimpermeable sleeve 280 to the enclosure 271. The semipermeable body 232and the liquid impermeable sleeve 280 are, therefore, intended for atleast partial insertion into opening of the enclosure 271. The sealformed between the semipermeable body assembly 230 and the enclosure 271prevents liquid and other substances in the environment of use, besidesthe permeation liquid, from entering the osmotic delivery system 270while also preventing materials from the inside of the delivery systemfrom leaking or escaping to the environment of use.

[0144] Because the liquid impermeable sleeve 280 abuts against orcontacts the entire cylindrical exterior surface 238 of thesemipermeable body 232, the cylindrical exterior surface 238 of thesemipermeable body is not immediately exposed to liquid when the osmoticdelivery system 270 is located in the liquid environment of use. Theliquid impermeable sleeve 280 may be fixed to the exterior surface 238of the semipermeable body 232 by an interference fit, an adhesive, orother means for attaching the liquid impermeable sleeve to thesemipermeable body. The liquid impermeable sleeve 280 acts as a barrieror seal to prevent liquid from the environment of use from immediatelyand directly contacting the exterior surface 238 of the semipermeablebody 232 when the osmotic delivery system 270 is first exposed to liquidfrom the environment of use.

[0145] The liquid impermeable sleeve 280 is separate and distinct fromthe enclosure 271 (it is not integral with the enclosure), and surroundsonly a portion of the entire peripheral surface (the cylindricalexterior surface 238 and end faces) of the semipermeable body 232 suchthat this surrounded portion of the peripheral surface is notimmediately exposed to liquid when the osmotic delivery system islocated in a liquid environment of use. As illustrated in FIG. 13, theliquid impermeable sleeve surrounds only the cylindrical exteriorsurface 238 of the semipermeable body 232 such that the cylindricalexterior surface 238 is not immediately exposed to liquid when theosmotic delivery system is located in a liquid environment of use. Whenthe osmotic delivery system 270 is inserted into a liquid environment ofuse, liquid does not immediately contact the entire cylindrical exteriorsurface 238 of the semipermeable body because it cannot traverse throughthe liquid impermeable sleeve 280 or immediately travel along theinterior surface of the sleeve. Of course, after the permeation liquidhas thoroughly soaked the semipermeable body 232, the entire exteriorsurface 238 of the semipermeable body 232 will have contacted theliquid, but this will not occur immediately after the osmotic deliverysystem is inserted in the liquid environment of use. The liquid from theenvironment of use will only travel along the interior surface of thesleeve after the liquid has entirely permeated through the semipermeablebody 232.

[0146] Because the liquid impermeable sleeve 280 does not abut againstthe entire peripheral surface of the semipermeable body 232, thesemipermeable body 232 includes an exposure or liquid contact surface248 defined by an area of the peripheral surface of the semipermeablebody that is not in contact with or surrounded by the liquid impermeablesleeve 280. Thus, the exposure surface 248 is immediately exposed toliquids when the osmotic delivery system 270 is located in the liquidenvironment of use, while the outer or exterior surface 238 is notimmediately exposed to liquid when the osmotic delivery system islocated in the liquid environment of use because the liquid impermeablesleeve 280 prevents the liquid from immediately contacting any surfaceof the semipermeable body 232 it is abutting. In other words, thepermeation liquid may only travel through the semipermeable body 232 byfirst contracting the liquid contact surface 248, not the cylindricalouter surface 238. Because the embodiment of the present inventionillustrated in FIG. 13 includes a tubular liquid impermeable sleeve 280,the exposure surface 248 only includes that portion of the semipermeablebody 232 that is incident to the cylindrical surface 238. The exposuresurface 248 is substantially perpendicular to the cylindrical surface238.

[0147] As described earlier, the beneficial delivery rate dMt/dt througha semipermeable body may be approximated by the following formula:

dMt/dt=dV/dt•C={P A Δπ/L}•C

[0148] In the embodiments of the present invention illustrated in FIGS.13-20, the liquid permeation rate through the semipermeable bodies 232,332, 432, 532, 632, 732, 832, (932, 932′, 932″) may be changed accordingto the above formula by varying the surface area of each of thesemipermeable body that is exposed to liquid and/or the thickness ofeach of the semipermeable bodies 232, 332, 432, 532, 632, 732, 832,(932, 932′, 932″).

[0149] As illustrated in FIG. 13, the semipermeable body 232 includestwo opposing flat ends, one located within the enclosure 271, and theother located outside the enclosure and defining the exposure surface248. Once the semipermeable body 232 and the liquid impermeable sleeve280 surrounding the semipermeable body are inserted into the enclosure271, the semipermeable body 232 is in liquid communication with theinterior of the liquid impermeable enclosure 271 to permit liquid fromthe environment of use to permeate through the semipermeable body 232 tothe osmotic agent 278 within the enclosure.

[0150] As described above in reference to the osmotic delivery system70, the liquid permeation rate through the semipermeable body 32 may becontrolled by varying the effective thickness L of the semipermeablebody 32. In the embodiment of the present invention illustrated in FIG.13, the liquid permeation rate through the semipermeable body 232 may becontrolled or changed by varying the thickness of the semipermeable body232. For example, by decreasing the thickness of the semipermeable body232, the liquid permeation rate through the semipermeable body 232 willincrease to correspondingly increase a delivery rate of the beneficialagent 272 from the osmotic delivery system 270. This may be achieved byfirst forming, such as by injection molding, the semipermeable body 232from a semipermeable material having a predetermined liquid permeabilitycoefficient. The semipermeable body 232 may also be formed with a set orpredetermined longitudinal length or thickness that corresponds to apredetermined or desired liquid permeation rate. The semipermeable body232 may also be formed with a predetermined diameter that defines asurface area of the liquid contact surface 248 and also corresponds to apredetermined or desired liquid permeation rate.

[0151] After the semipermeable body 232 has been formed, the liquidpermeation rate through the semipermeable body 232 may be increased bydecreasing the thickness of the semipermeable body. In the embodiment ofthe present invention illustrated in FIG. 13, the semipermeable body 232surrounded by the liquid impermeable sleeve 280 may be cut to increasethe liquid permeation rate through the semipermeable body, i.e., thethickness of the semipermeable body 232 is decreased to increase theliquid permeation rate through the semipermeable body 232. Asillustrated in FIG. 13, the portion of the liquid impermeable sleeve 280and semipermeable body 232 protruding from the enclosure 271 has a firstlength X, which may be decreased to a second length X′ to increase theliquid permeation rate through the semipermeable body 232. The thicknessor length of the semipermeable body 232 may be changed before or afterthe semipermeable body assembly 230 has been inserted into the openingof the enclosure 271. The exterior surface of the liquid impermeablesleeve 280 may include indicia spaced along the length of the sleevethat respectively indicate a location where the semipermeable body maybe cut to achieve a desired liquid permeation rate or beneficial agentdelivery rate.

[0152] The semipermeable body 232 and the sleeve 280 can be moldedtogether such that the two items are “preassembled” and form the osmoticdelivery system semipermeable assembly 230. For example, the liquidimpermeable sleeve may be laminate outer coating on the semipermeablebody 232. The semipermeable body 232 can also be inserted into thesleeve 280 after it has been formed, in which case the sleeve 280 willmatingly receive the semipermeable body 232. Accordingly, it should berealized that the length of the sleeve 280 and the semipermeable body232 may be decreased separately and then assembled to form thesemipermeable body assembly 230. Alternatively, the length of thesemipermeable body assembly 230 (semipermeable body 232 and liquidimpermeable sleeve 280) can be decreased by simultaneously decreasingthe length of the semipermeable body and the liquid impermeable sleeve280. Any variety of techniques may be used to decrease the thickness ofthe semipermeable body 232 and sleeve 280, including shearing, cutting,tearing, laser slicing, grinding, etc.

[0153] As described above, by varying the thickness of the semipermeablebody 232, the liquid permeating rate through the body can be controlled.This is beneficial because, for example, different desired liquidpermeation rates through the semipermeable body 232 are obtainable fromsemipermeable bodies 232 formed from the same material having the samepermeability coefficient and liquid uptake characteristics. Thus, it ispossible to obtain a multitude of different liquid permeation rates, andthus different beneficial agent delivery rates by simply decreasing thethickness of one preformed semipermeable body. This is furtherbeneficial because biocompatability and toxicity tests need only beperformed on one semipermeable material.

[0154] Because the exposure surface 248 defines the only surface area ofthe semipermeable membrane body 232 that is immediately exposed toliquids when the osmotic delivery system is located in its environmentof use, the liquid permeation rate through the semipermeable body 232may be easily increased by simply decreasing the length of thesemipermeable body 232 and liquid impermeable sleeve 280. If the sleeve280 and semipermeably body 232 are cut along a line perpendicular to thelongitudinal axis of the sleeve and body, the exposure surface area willremain constant such that the increase in liquid permeation rate throughthe decreased length semipermeable assembly 230 may be easily estimated.Thus, an administrator of the osmotic delivery system 270 may change andestimate the permeation rate through the semipermeable body 230 toachieve a desired permeation rate by simply cutting or slicing onesemipermeable body 232, rather than having to choose a differentsemipermeable body for each desired application.

[0155] The liquid permeation rate through the semipermeable body 232 mayalso be controlled or varied by removing a portion of the liquidimpermeable sleeve 280 from the exterior surface 238 of thesemipermeable body to increase the amount of surface area of thesemipermeable body 232 that is immediately exposed to liquids when theosmotic delivery system 270 is located in its environment of use. Thismay be achieved by cutting through the liquid impermeable sleeve 280,but not the semipermeable body 232, and then removing the portion of thesleeve directly adjacent to the cut. Thus, the exposure surface willthen include the end surface and a portion of the cylindrical exteriorsurface 238. Increasing the amount of exposure surface area willincrease the liquid permeation rate through the semipermeable body 232.

[0156] In the above described manner, the liquid permeation rate throughthe semipermeable membrane 232 can be controlled. Although notillustrated, the semipermeably assembly 230 may also be configured witha recess and insert like the plug 30 illustrated in FIG. 7. This isfurther advantageous because a low liquid uptake membrane material canbe used for the semipermeable body 232, while still permitting theliquid permeation rate to be controlled.

[0157]FIG. 14 illustrates another embodiment of an osmotic deliverydevice or system 370. As illustrated in FIG. 14, the osmotic deliverysystem 370 includes an elongated cylindrical enclosure 371 having anopening through which a semipermeable body assembly 330 has beeninserted. The semipermeable body assembly 330 includes the semipermeablebody 332 and the liquid impermeable sleeve 380, similar to thesemipermeable body 232 and liquid impermeable sleeve 280 illustrated inFIG. 13. The enclosure 371 receives the osmotic agent 378, which drivesthe osmotic flow of the osmotic delivery device 370.

[0158] As illustrated in FIG. 14, only the semipermeable body 332 hasbeen inserted into to the opening of the enclosure 371. The liquidimpermeable sleeve 380 is not located within the enclosure 371 becauseit has not been inserted in the opening of the enclosure. The osmoticagent 378 is directly adjacent to or abuts against the semipermeablebody 332. The semipermeable body 332 allows liquid to pass from anenvironment of use into the enclosure 371 to cause the osmotic agent 378to swell. The semipermeable body 332 and the liquid impermeable sleeve380 together define an osmotic delivery system semipermeable bodyassembly 330 that controls a delivery rate of beneficial agent from theosmotic delivery system 370. The configuration of the semipermeable body332 and the liquid impermeable sleeve 380 dictates the liquid permeationrate through the semipermeable body, which generally controls thedelivery rate of the beneficial agent (not illustrated) from the osmoticdelivery system 370.

[0159] The semipermeable body 332 is cylindrical shaped, like thesemipermeable body 232 illustrated in FIG. 13, and is sized such that itis matingly received by an opening in the enclosure 371. As illustratedin FIG. 14, the semipermeable body 332 includes a plug end 333 having aseries of ridges or ribs 334 which form a seal with the interior surfaceof the enclosure 371. However, contrary to the osmotic delivery systemillustrated in FIG. 13, the liquid impermeable sleeve 380 is notinserted into the enclosure 371. The liquid impermeable sleeve 380 islocated external of the enclosure 371. The liquid impermeable sleeve 380abuts against the exterior surface 338 of the semipermeable body 332such that the cylindrical exterior surface 338 of the semipermeable bodyis not immediately exposed to liquid when the osmotic delivery system370 is located in the liquid environment of use. Liquid from theenvironment of use is also not allowed to substantially penetrate thejoint between the sleeve 380 and the enclosure 371. Because the liquidimpermeable sleeve 380 is not inserted into the enclosure 371, thesemipermeable body 332 alone operates like a cork or stopper when it isinserted into the enclosure 371 of the osmotic delivery system 370,similar to the plug 30 illustrated in FIG. 7.

[0160] Like the liquid impermeable sleeve 280, the liquid impermeablesleeve 380 is separate from the enclosure 271, and surrounds only aportion of the entire peripheral surface of the semipermeable body 332such that a portion of the peripheral surface is not immediately exposedto liquid when the osmotic delivery system is located in the liquidenvironment of use. Because the liquid impermeable sleeve 380 does notabut against the entire peripheral surface of the semipermeable body323, the semipermeable body includes an exposure or liquid contactsurface 348 defined by an area of the peripheral surface that is notsurrounded by the liquid impermeable sleeve 380 and is located externalof the enclosure 371. The exposure surface 348 is immediately exposed toliquids when the osmotic delivery system 370 is located in the liquidenvironment of use.

[0161] The liquid permeation rate through the semipermeable body 332 ofthe osmotic delivery system 370 may be controlled or changed by varyingthe thickness of the semipermeable body 332. For example, the liquidpermeation rate through the semipermeable body 332 may be changed toincrease a delivery rate of the beneficial agent from the osmoticdelivery system. The liquid permeation rate through the semipermeablebody 332 may be increased by decreasing the thickness of thesemipermeable body by, for example, cutting the semipermeable body. Thesemipermeable body 332 may be cut before or after it has been insertedinto the enclosure 371. When cutting the semipermeable body 332, theliquid impermeable sleeve 380 may also be cut. That is, both the liquidimpermeable sleeve 380 and the semipermeable body 332 may be cut in oneaction to decrease the thickness of both the liquid impermeable sleeveand the semipermeable body 332 in the longitudinal direction of thesemipermeable body, i.e., parallel with the cylindrical surface 338 ofthe semipermeable body 332.

[0162] The liquid permeation rate through the semipermeable body 332 mayalso be controlled by increasing the amount of surface area of thesemipermeable body that is immediately exposed to liquids when theosmotic delivery system 370 is placed in its environment of use. Theliquid permeation rate may be increased by removing a portion of theliquid impermeable sleeve 380 such that the amount of exposure surface348 that is exposed to liquids is increased.

[0163] The liquid impermeable sleeve 380 can be fixed to thesemipermeable body 332 by an adhesive or other means that prevent thesleeve from moving relative to the semipermeable body 332.Alternatively, the sleeve 332 can be moveable relative to the body 332,although still contacting the cylindrical exterior surface 338 of thesemipermeable body.

[0164]FIG. 15 illustrates another embodiment of an osmotic deliverysystem 470 according to the present invention. The osmotic deliverysystem 470 includes an enclosure 471 having an opening through which asemipermeable body 432 of a semipermeable body assembly 430 has beeninserted. The semipermeable body 432 is similar to the semipermeablebody 332 illustrated in FIG. 14 as the semipermeable body 432 includes aplug end 433 that has been inserted into the enclosure 471. Thus, only aportion of the semipermeable body 432 has been inserted into theenclosure 471. The semipermeable body 432 allows liquid to pass from anenvironment of use into the enclosure 471 to cause the osmotic agent 478to swell and move the piston 474. The semipermeable body 432 and theliquid impermeable sleeve 480 together define the semipermeable bodyassembly 430 that controls a delivery rate of beneficial agent from theosmotic delivery system 470. The configuration of the semipermeable body432 and the liquid impermeable sleeve 480 dictates the liquid permeationrate through the semipermeable body, which generally controls thedelivery rate of the beneficial agent from the osmotic delivery system470.

[0165] The liquid impermeable sleeve 480 is tubular, and abuts againstthe cylindrical exterior surface 438 of the cylindrical semipermeablebody 432. In the embodiment of the present invention illustrated in FIG.15, the liquid impermeable sleeve 480 is not inserted within theenclosure 471, and is thus located external of the enclosure. The liquidimpermeable sleeve 480 is fixedly attached to the exterior surface ofthe enclosure 471 as well as the exterior surface of the semipermeablebody 432. The liquid impermeable sleeve 480 is fixedly attached to thesemipermeable body 432 such that the liquid impermeable sleeve and thesemipermeable body are not movable with respect to each other. Theliquid impermeable sleeve 480 may be fixed to the semipermeable body 432by an adhesive, weld, bonding agent or other similar device for securingor fastening the sleeve to the body.

[0166] The liquid impermeable sleeve 480 also forms a seal between theenclosure 471 and the sleeve 480 when the liquid impermeable sleeve 480is positioned over the enclosure 471 and is affixed to the exteriorsurface of the enclosure. Thus, the liquid impermeable sleeve 480 isalso not movable relative to the enclosure 471. Because the liquidimpermeable sleeve 480 forms a seal or a watertight joint with theenclosure 470, the semipermeable body 432 need not include the plug end433. In such an embodiment, the semipermeable body 432 is locatedentirely external of the enclosure 471, and the seal between the liquidimpermeable sleeve 480 and the enclosure 471 prevents liquid and othersubstances in the environment of use, besides the permeation liquid,from entering the osmotic delivery system 470 while also preventingmaterials from the inside of the delivery system from leaking orescaping to the environment of use.

[0167] The liquid permeation rate through the semipermeable body 432 maybe increased by changing the thickness of the semipermeable body 432 andthus the liquid permeation rate through the semipermeable body, similarto the embodiments illustrated in FIGS. 13 and 14. For instance, thesemipermeable body 432 may be cut to increase the liquid permeation ratethrough the semipermeable body.

[0168]FIG. 16 illustrates another embodiment of an osmotic deliverydevice or system 570. As illustrated in FIG. 16, the osmotic deliverysystem 570 includes an elongated cylindrical enclosure 571 having anopening through which a semipermeable body 532 has been inserted. Thesemipermeable body 532 is a cylindrical plug of semipermeable materialhaving a series of rigid or ribs to help effect a seal between thesemipermeable body and the interior surface of the liquid impermeableenclosure 571. The enclosure 571 also receives the osmotic agent 578,which drives the osmotic flow of the osmotic delivery device 570 bymoving the piston 574.

[0169] The semipermeable body 532 is not surrounded by a liquidimpermeable sleeve that is separate and distinct from the enclosure 571.The semipermeable body 532 is only surrounded by the enclosure 571,similar to the semipermeable body 32 shown in FIG. 7. However, theenclosure 571 includes a plurality of grooves, channels, furrows,recesses or indentations 581 which define predetermined cuttinglocations by which an administrator can decrease the length of theenclosure 571 and the thickness of the semipermeable body 532. That is,the semipermeable body 532 surrounded by the enclosure 571 may be cut toincrease the liquid permeation rate through the semipermeable body,i.e., the “effective thickness” L of the semipermeable body 532 isdecreased. In this manner, the liquid permeation rate through thesemipermeable body 532 may be varied to control the beneficial agentdelivery rate from the osmotic delivery system 570.

[0170] As illustrated in FIG. 16, the indentations or grooves 581 definea plurality of 360° recesses that each lie on a plane approximatelyperpendicular to the longitudinal axis of the enclosure 571 (parallelwith the exterior surface of the semipermeable body 532). Anadministrator may cut the enclosure 571 and the semipermeable body 532along a plane that includes one of the grooves 581 such that the surfacearea of the exposure surface 548 will remain constant. By keeping thesurface of the exposure surface 548 constant, the increase in liquidpermeation rate through the semipermeable body 532 may be easilyestimated when an administrator decreases the length of thesemipermeable body 532 by cutting completely through one of the grooves581. For instance, each of the grooves 581 may correspond to apredetermined or desired liquid permeation rate and/or a predeterminedor desired beneficial agent delivery rate from the osmotic deliverysystem 570. Thus, an administrator of the osmotic delivery system 570may easily change the permeation rate through the semipermeable body bysimply cutting or slicing the semipermeable body 532 and the enclosure571 along one of the grooves 581. The exterior surface of the enclosure571 may include indicia indicating a desired permeation rate thatcorresponds to the respective groove 581.

[0171]FIG. 17 illustrates another embodiment of an osmotic deliverysystem 670 according to the present invention. As illustrated in FIG.17, the osmotic delivery system 670 includes an elongated cylindricalenclosure 671. The osmotic delivery system 670 includes thesemipermeable body assembly 630 having the semipermeable body 632 andliquid impermeable sleeve 680. As illustrated in FIG. 17, thesemipermeable body 632 and the liquid impermeable sleeve 680 are bothexternal of the enclosure 671. The semipermeable body 632 is notpositioned within the enclosure 671, and is larger than the opening intothe enclosure 671 such that may not be easily inserted into theenclosure. However, the osmotic delivery system 670 could be configuredto receive a portion of the semipermeable body 632, such as illustratedin FIGS. 14 and 15. The enclosure 671 receives the osmotic agent 678 andthe movable piston 674 and the osmotic agent 678 drives the osmotic flowof the osmotic delivery device 670.

[0172] As illustrated in FIG. 17, the semipermeable body 632 is locatedwithin the liquid impermeable sleeve 680 and the sleeve is longer thanthe semipermeable body. The liquid impermeable sleeve 680 is threadedonto the enclosure 671 via the threads 682. The liquid impermeablesleeve 680 may include threads that engage the exterior surface of theenclosure 671, the enclosure may include threads that engage theinterior surface of the liquid impermeable sleeve, or both the liquidimpermeable sleeve and the exterior surface of the enclosure may includethreads that matingly engage each other. Because the sleeve 680 isthreadable onto and off of the enclosure 671, the liquid impermeablesleeve 680 is rotatable with respect to the enclosure 671. Thus, theliquid impermeable sleeve 680 may be moved linearly with respect to theenclosure 671 by rotating the sleeve with respect to the enclosure aboutthe longitudinal axis of the enclosure via the threads 682. The liquidimpermeable sleeve 680 may be moved longitudinally along thelongitudinal axis of the enclosure 671, i.e., along an axis parallelwith the cylindrical wall of the enclosure, by rotating the sleeve onthe threads 682.

[0173] Because the diameter of the semipermeable body 632 is larger thanthat of the opening into the enclosure 671, when the liquid impermeablesleeve is threaded onto the enclosure 671 such that the liquidimpermeable sleeve moves linearly toward the enclosure, the surface areaof exposure surface 648 will increase, i.e., the peripheral surface areaof the semipermeable body that is not touching or contacting the liquidimpermeable sleeve will increase. Thus, the surface area of thesemipermeable membrane body 632 that is immediately exposed to liquidswhen the osmotic delivery system is located in its environment of usemay be increased by threading the liquid impermeable sleeve 680 onto theenclosure 671 such that the sleeve 680 moves with respect to thesemipermeable body 632 and the enclosure 671.

[0174] The semipermeable body 632 is positioned within the liquidimpermeable sleeve 680 such that the liquid impermeable sleeve may moverelative to the semipermeable body 632. For example, the liquidimpermeable sleeve 680 may receive the semipermeable body 632 and aninterference fit manner sufficiently tight to retain the semipermeablebody within the liquid impermeable sleeve, while permitting the liquidimpermeable sleeve 680 to slidingly move relative to the semipermeablemembrane when the liquid impermeable sleeve is threaded onto theenclosure 671. However, the portion of the liquid impermeable sleeve 680that abuts against the cylindrical exterior surface of the semipermeablebody 632 is not immediately exposed to liquid when the osmotic deliverysystem 670 is located in a liquid environment of use. When the liquidimpermeable sleeve 680 is threaded onto the enclosure 671, the exposuresurface 648 will include more than the flat surface of the semipermeablebody that is perpendicular to the liquid impermeable sleeve 680. Forexample, as the liquid impermeable sleeve 680 is threaded onto theenclosure 671 such that it moves toward the enclosure 671, a portion ofthe cylindrical exterior surface 638 of the semipermeable body 632 maybe exposed to increase the liquid permeation rate through thesemipermeable body.

[0175] By threading the liquid impermeable sleeve 680 toward theenclosure 671, an administrator may increase the surface area of thesemipermeable body that is exposed to liquids when the osmotic deliverysystem 670 is placed in its environment of use. After the sleeve 680 hasbeen moved toward the enclosure 671, the exposure surface 648 will thusbe cap-shaped, rather than flat. Thus, it is apparent that the liquidpermeation rate through the semipermeable body 632 may be varied bychanging the exposure surface area of the semipermeable body. FIG. 18illustrates another embodiment of the present invention that operatesunder a similar principle.

[0176] As illustrated in FIG. 18, the osmotic delivery system 770includes an elongated substantially cylindrical enclosure 771 having anopining through which a semipermeable body 732 has been inserted. Thesemipermeable body 732 is part of a semipermeable body assembly 730 thatincludes the liquid impermeable sleeve 780. Within the enclosure 771 ofthe osmotic delivery system 770 is the beneficial agent 772 to bedelivered, and a movable piston 774. The osmotic agent 778 within theenclosure 771 is separated from the beneficial agent by the movablepiston 774. The enclosure 771 receives the osmotic agent 778, whichdrives the osmotic flow of the osmotic delivery system 770.

[0177] As illustrated in FIG. 18, the osmotic delivery device 770includes the semipermeable body 732 and the liquid impermeable sleeve780. The semipermeable body 732 includes an insert 760, similar to theplug 30 illustrated in FIG. 7. Each of the semipermeable bodies 232,332, 432, 632, 732, 832 illustrated in FIGS. 13-20 may include an insertthat is received by a recess formed in the semipermeable body.

[0178] The semipermeable body 732 allows liquid to pass from anenvironment of use into the enclosure 771 to cause the osmotic agent 778to swell. The semipermeable body 732 and the liquid impermeable sleeve780 together define an osmotic delivery system semipermeable bodyassembly 730 that controls the delivery rate of beneficial agent 772from the osmotic delivery system 770. The configuration of thesemipermeable body 732 and position of the liquid impermeable sleeve 780dictates the liquid permeation rate through the semipermeable body,which generally controls the delivery rate of the beneficial agent 772from the osmotic delivery system 770.

[0179] As illustrated in FIG. 18, the semipermeable body 732 issurrounded by the tubular liquid impermeable sleeve 780. The interiorsurface of the liquid impermeable sleeve 780 abuts against thecylindrical surface 738 of the semipermeable body 732 and the respectivesurfaces are moveable relative to each other such that the interiorsurface of the liquid impermeable sleeve slides relative to the exteriorsurface of the semipermeable body 732. As in the previous embodiments ofthe present invention, the liquid impermeable sleeve 780 abuts againstthe exterior surface of the semipermeable body 732 such that the surfacearea of the semipermeable body against which the liquid impermeablesleeve abuts is not immediately exposed to liquid when the osmoticdelivery system is located in the liquid environment of use.

[0180] The liquid impermeable sleeves 780 is movable relative to thesemipermeable body 732, as well as the enclosure 771 of the osmoticdelivery system 770. For example, the liquid impermeable sleeve 780 ismovable from the position Y to the position Y′ with respect to thesemipermeable body 732 along the longitudinal direction of the enclosure771. In this manner, the amount of surface area of exposure surface 748that is immediately exposed to liquids when the osmotic delivery system770 is located in its environment of use may be increased. The liquidpermeation rate through the semipermeable body 732 may be controlled byincreasing the amount of surface area of the semipermeable body 732 thatis exposed to liquids when the osmotic delivery system is placed in itsenvironment of use. An administrator may move or slide the liquidimpermeable sleeve 780 upward or downward relative to the enclosure 771and the semipermeable body 732 to vary the liquid permeation ratethrough the semipermeable body 732.

[0181] In the embodiment of the present invention illustrated in FIG.18, the liquid impermeable sleeve 780 is fitted to the enclosure 771 viaa tight interference fit. The liquid impermeable sleeve 780 matinglyengages the exterior surface of the enclosure 771 such that it may slidewith respect to the exterior surface of the enclosure. Although theliquid impermeable sleeve 780 is fitted to the enclosure 771 via aninterference fit, the liquid impermeable sleeve may also be movablyfitted or movably attached to the enclosure 771 via other means. Forexample, the liquid impermeable sleeve 780 may be movably attached tothe enclosure 771 through grooves, threads, or other similar devices.The exterior surface of the enclosure 771, the interior surface of thesleeve 780, or both the exterior surface of the enclosure and interimsurface of the sleeve may include grooves, ridges, or lips to assist andcontrol relative movement between the liquid impermeable 780 sleeve andthe enclosure 771.

[0182] The semipermeable body 732 may be inserted into the opening ofthe enclosure 771, and thereafter, the liquid impermeable sleeve 780 maybe slid over the semipermeable body 732 and the enclosure 771 to adesired position that exposes an amount of exposure surface 748 thatcorresponds to a desired liquid permeation rate though the semipermeablebody 732. Alternatively, the sleeve 780 may be slid over thesemipermeable body 732 to a desired position that exposes an amount ofexposure surface 748 that corresponds to a desired liquid permeationrate through the semipermeable body 732 before the semipermeable bodyassembly 730 is positioned in the enclosure 771. After the liquidimpermeable sleeve 780 has been positioned to its desired location, anadhesive can be used to bond the liquid impermeable sleeve to theenclosure 771, such that it is not longer movable with respect to theenclosure 771 and the semipermeable body 732.

[0183]FIG. 19 illustrates another embodiment of an osmotic deliverysystem 870 according to the present invention. As illustrated in FIG.19, the semipermeable body assembly 830 includes a liquid impermeablesleeve 880 and a semipermeable body 832. The semipermeable body 832 hasbeen inserted into the enclosure 871 of the osmotic delivery system 870.The semipermeable body 832 allows liquid to pass from an environment ofuse into the enclosure 871 to cause the osmotic agent 878 to swell anddrive the piston 874. The osmotic tablet 878 thus drives the osmoticflow of the osmotic delivery device 870. As illustrated in FIG. 19, theliquid impermeable sleeve 880 includes threads 882 on its interiorsurface. The liquid impermeable sleeve 880 is configured similar to apipe or conduit that has threads on its interior surface. The threads882 extend along the center axis of the liquid impermeable sleeve 880such that the entire interior surface of the tubular sleeve includes thethreads 882. Thus, the liquid impermeable sleeve 880 may be threadedonto the semipermeable body 832 via the threads 882. A portion of thesemipermeable body 832 extends from the enclosure 871 such that theliquid impermeable sleeve 880 may be threaded onto the semipermeablebody. The liquid impermeable sleeve 880 is separate from the enclosure871 and abuts against or surrounds only a portion of the entireperipheral surface of the semipermeable body 832 such that at least aportion of the peripheral surface of the semipermeable body is notimmediately exposed to liquid when the osmotic delivery system islocated in a liquid environment of use.

[0184] The liquid permeation rate through the semipermeable body 832 maybe controlled by increasing the amount of surface area of thesemipermeable body that is immediately exposed to liquids when theosmotic delivery system 870 is placed in its environment of use. Forexample, the liquid permeation rate may be increased by partiallyunthreading or partially removing the liquid impermeable sleeve 880 fromthe portion of the semipermeable body 832 that extends from theenclosure 871. That is, the liquid permeation rate may be increased byincreasing the exposure surface area of the semipermeable membrane body832 that is immediately exposed to liquids when the osmotic deliverysystem is located in its environment of use. An administrator maypartially unthread the liquid impermeable sleeve 880 from thesemipermeable body 832 to increase the exposure surface area 848. Asillustrated in FIG. 19, by partially unthreading the sleeve 880, theliquid contact surface or exposure surface 848 will include a portion ofthe cylindrical exterior surface of the semipermeable body 832 as wellas the flat end surface of the semipermeable body 832 that isperpendicular to the cylindrical exterior surface of the semipermeablebody. However, because the end surface is always exposed to liquids whenthe osmotic delivery system 870 is located in a liquid environment ofuse, the liquid permeation rate through the semipermeable body 832 isincreased by increasing the amount of the cylindrical surface area ofthe semipermeable body that is immediately exposed to liquids when theosmotic delivery system 870 is located in its environment of use.

[0185] The liquid impermeable sleeve 880 can also be threaded onto thesemipermeable body 832 to decrease the amount of cylindrical surfacearea of the semipermeable body that is immediately exposed to liquidswhen the osmotic delivery system is located in its environment of use.The liquid permeation rate through the semipermeable body 832 may bedecreased by threading the liquid impermeable sleeve 880 onto thesemipermeable body 832 to decrease an amount of cylindrical surface areathat is immediately exposed to liquid when the osmotic delivery systemis located in its environment of use. Although the liquid impermeablesleeve includes the threads 882, alternative means for fastening theliquid impermeable sleeve 880 to the semipermeable body 832 arecontemplated. For example the liquid impermeable sleeve 880 may fit ontothe semipermeable body 832 via an interference fit. However, the sleeve880 preferably does not overly compress the semipermeable body 832 suchthat the liquid permeation rate through the semipermeable body isaffected.

[0186] The osmotic delivery system 870 may come assembled with thesemipermeable body 832 extending from the enclosure 871, and anadministrator may choose a liquid impermeable sleeve 880 that may befitted over the semipermeable body 832 to vary the liquid permeationrate through the semipermeable body in the above-described manner. Anadministrator of the osmotic delivery system 870 may control the liquidpermeation rate and hence the beneficial agent delivery rate from theosmotic delivery system 870 by simply varying the amount of surface areathat is exposed to liquids when the osmotic delivery system is locatedin its environment of use. An adhesive or other means may be used tosecure the liquid impermeable sleeve 880 to the semipermeable body afterit has been moved to its desired position relative to the exteriorsurface of the semipermeable body 832. As described above, by varyingthe amount of surface area that is immediately exposed to liquids whenthe osmotic delivery system 870 is located in its environment of use,the liquid permeation rate through the semipermeable body 832 can bevaried to control the beneficial agent delivery rate from the osmoticdelivery system 870. The thickness of the liquid impermeable sleeve 880and/or the semipermeable body 832 may also be decreased to change theliquid permeation rate through the semipermeable body.

[0187]FIG. 20 illustrates another embodiment of an osmotic deliverysystem 970 according to the present invention. The osmotic deliverysystem 970 includes an elongated substantially cylindrical enclosure 971having an opening through which an osmotic tablet 978 and a piston 974have been inserted. The osmotic delivery system 970 includes a firstsemipermeable body 932, as well as an optional second semipermeable body932′ and optional third semipermeable body 932″. The first semipermeablebody 932, and optionally the second and third semipermeable bodies 932′and 932″, are in liquid communication with the enclosure 971 such thatliquids may permeate through the semipermeable bodies 932 to the osmoticagent 978 and drive the osmotic flow of the osmotic delivery system 970.The end of the enclosure 971 opposite the opening through which theosmotic agent 978 has been inserted has one or more delivery ports 975for delivering the beneficial agent 972 from the osmotic delivery system970. The osmotic agent 978 within the enclosure 971 is separated fromthe beneficial agent 972 by the movable piston 974.

[0188] As illustrated in FIG. 20, the osmotic delivery device 970includes at least the first semipermeable body 932. The firstsemipermeable body 932 is part of or integral with the firstsemipermeable body element 983. The first semipermeable body element 983includes the first semipermeable body 932 as well as the wall portion980. The wall portion 980 is a layer of liquid impermeable material thatholds the first semi-permeable body 932. The first semipermeable body932 is not located within the opening of the enclosure 971. However, thesemipermeable body 932 is generally directly adjacent or touching theosmotic agent 978.

[0189] The first semipermeable body 932 of the first semipermeable bodyelement 983 allows liquid to pass from an environment of use into theenclosure 971 to cause the osmotic agent 978 to swell. The firstsemipermeable body 932 controls a delivery rate of beneficial agent 972from the osmotic delivery system 970. More specifically, the thickness tand surface area of the exposure surface 948 of the semipermeable body932 that is immediately exposed to liquids when the osmotic deliverysystem 970 is located in a liquid environment of use dictates the liquidpermeation rate through the first semipermeable body 932, whichgenerally controls the delivery rate of the beneficial agent from theosmotic delivery system 970.

[0190] As illustrated in FIG. 20, the first semipermeable body 932 isgenerally disc-shaped, such as a nickel or dime with one of its flatsurfaces abutting against the osmotic agent 978 within the enclosure971. The other flat surface defines the exposure surface 948. The firstwall portion 980 of the first semipermeable body element 983 is tubularor cup-shaped and holds the first semipermeable body 932. Thesemipermeable body 932 generally defines the bottom of the cup-shapedsemipermeable body element 983. The tubular wall portion 980 includes arecess that receives the enclosure 971.

[0191] The first semipermeable body 932 and the first wall portion 980can be molded in a single operation to define a unified structure thefirst semipermeable body element 930. Alternatively, the firstsemipermeable body 932 may be inserted into a preformed opening in thefirst wall portion 980 to form the semipermeable body element 930. Aseal is located between the first semipermeable body 932 and the firstwall portion 980 such that the interface is water-tight. The interiorsurface of the first wall portion 980 attaches to the exterior surfaceof the enclosure 971 such that the first semipermeable body 932, held bythe first wall portion 980, is also attached to the enclosure 971.

[0192] Although the first wall portion 980 of the first semipermeablebody element 983 illustrated in FIG. 20 is tubular, it may be otherconfigurations. For example, the first wall portion 980 and firstsemipermeable body 932 may be rectangular and together define the shapeof a rectangular adhesive bandage such as a BAND-AID brand adhesivebandage. This configuration is particularly suitable for osmoticdelivery systems that already include a semipermeable plug that sealsthe enclosure, such as that illustrated in FIG. 1. Such a semipermeablebody element need not prevent materials from the exterior environmentfrom entering the interior of the enclosure 971, as the semipermeableplug inserted in the enclosure of the osmotic delivery device alreadyseals the enclosure from external materials, except for the permeationliquid.

[0193] The material forming the first wall portion 980 is liquidimpermeable, similar to the liquid impermeable sleeves described above.The wall portion 980 is preferably formed from a material that islargely impermeable to the materials within the enclosure 971 and otheringredients within the environment of use. The wall portion 980 ispreferably substantially impermeable to liquid in the environment of useas well as to ingredients contained within the osmotic delivery system970 such that the migration of such materials into or out of the osmoticdelivery system through the wall portion 980 is so low as to havesubstantially no adverse impact on the function of the osmotic deliverydevice. The wall portion 980 can also be formed from a flexible materialsuch that it is conformable to the exterior surface of the enclosure971.

[0194] The cylindrical interior surface of the first wall portion 980that contacts the exterior surface of the enclosure 971 forms a sealwith the exterior surface of the enclosure 971. The seal between thewall portion 980 and the enclosure 971 may be enhanced by threads orribs in the interior surface of the wall portion 980 or the exteriorsurface of the enclosure 971. The seal between the first wall portion980 and the enclosure 971 may be achieved by a tight interference fit,or an adhesive. Together, first the semipermeable body 932 and the firstwall portion 980 of the first semipermeable body element 983 preventliquid and other substances in the environment of use, besides thepermeation liquid, from entering the osmotic delivery system 970 whilealso preventing materials from the inside of the delivery system fromleaking or escaping to the environment of use.

[0195] As illustrated in FIG. 20, the osmotic delivery system 970 mayinclude a plurality of semipermeable body elements 983, 983′, 983″. Thesemipermeable body elements 983, 983′, 983″ may be positioned inabutting relationship to one another to define a “net semipermeablebody” of increased thickness to achieve a desired liquid permeation ratethrough the net semipermeable body. That is, an additional or secondsemipermeable body element 983′ may be added to the osmotic deliverysystem 970 to achieve a different and desired liquid permeation rate.The second semipermeable body element 983′ may be positioned adjacent tothe first semipermeable body element 983 such that the secondsemipermeable body 932′ is located in abutting or contacting relation tothe first semipermeable body 932. Together, the first semipermeable body932 and the second semipermeable body 932′ form a net semipermeable bodyof the osmotic delivery system 970 having a liquid permeation ratedifferent from that of the first semipermeable body 932 alone. Forexample, the liquid permeation rate through the net semipermeable bodyof the osmotic delivery system 970 may be decreased by increasing the“effective thickness” L of the net semipermeable body by providing twoof the semipermeable bodies 932, 932′ in abutting relation to oneanother. By positioning the second semipermeable body element 983′directly adjacent to the first semipermeable body element 983 such thatthe first and second semipermeable bodies 932, 932′ contact, the secondsemipermeable body 932′ is “stacked” or layered on the firstsemipermeable body 932 to define a net semipermeable body of greaterthickness than either of the first and second semipermeable bodiesalone. This may be achieved by positioning the second wall portion 980′of the second semipermeable body element 983′ directly over the firstwall portion 980 of the first semipermeable body element 983, similar toplacing a first drinking cup on top of a second identical drinking cupsuch that the second cup receives the first cup.

[0196] The second wall portion 980′ may be affixed or attached to theexterior surface of the first wall portion 980′ of the firstsemipermeable body element 983 via an adhesive or other means forsecuring or attaching the second wall portion 980 to the first wallportion 980 enclosure. For example, the second wall portion 980′ may berigid and thread onto the first wall portion 980 or may be flexible andstretch over the first wall portion 980.

[0197] The thickness of the net semipermeable body may be furtherincreased by positioning a third semipermeable body element 983″ on topof the first and second semipermeable body elements 983, 983′ such thatthe third semipermeable body 932″ is adjacent and abutting the secondsemipermeable body 932′. By positioning the semipermeable bodies 932,932′, 932″ in abutting relationship to one another, the semipermeablebodies are in liquid communication with each other so as to permitliquid to permeate through each of the semipermeable bodies 932, 932′,932″ to the osmotic agent 978. For example, with an osmotic deliverysystem 970 that includes three abutting or layered semipermeable bodyelements 983, 983′, 983″, liquid from an external environment of usewill first permeate through the first semipermeable body 932″ to thesecond semipermeable body 932′ and eventually through the firstsemipermeable body 932 such that the osmotic agent may swell and drivethe osmotic flow of the osmotic delivery system 970.

[0198] Conversely, if the assembled osmotic delivery system 970 includesa plurality of stacked semipermeable body elements 983′, 983″, theliquid permeation rate through the net semipermeable body of the systemmay be increased by removing one or more of the semipermeable bodyelements 983, 983′, 983″. For example, should the osmotic deliverysystem 970 include three semipermeable body elements 983, 983′, 983″,the liquid permeation rate through the system may be increased byremoving the third semipermeable body element 983″ such that thethickness of the net semipermeable body of the system is decreased.

[0199] As described above, the stacked semipermeable body elements 933,933′, 933″ form layers of semipermeable bodies 932, 932′, 932″. Byremoving or adding layers, the liquid permeation rate through the netsemipermeable body of the system 970 may be controlled or varied. Whenthe semipermeable bodies 932, 932′, 932″ are stacked or layered asdescribed above, the semipermeable bodies 932, 932′, 932″ are in liquidcommunication with the liquid impermeable enclosure 971 to permit liquidfrom the environment of use to permeate through all of the semipermeablebodies to the osmotic agent 978 within the enclosure 971.

[0200] If the wall portions 980, 980′, 980″ are made of a resilient orflexible material, the semipermeable body elements 983, 983′, 983″ canbe of identical construction while still stackable on each other suchthat only one semipermeable body element need be manufactured. Thus, avariety of liquid permeation rates may be achieved by stacking identicalsemipermeable body elements 983, 983′, 983″.

[0201] Although not illustrated, the second and third semipermeable bodyelements 983′, 983″ may include a semipermeable body 932′, 932″ that hasa greater exposure surface area than that of the first semipermeablebody 932. Likewise, the thicknesses of the second and thirdsemipermeable bodies 932′, 932″ in the axial or longitudinal directionof the enclosure 971 may vary. Thus, the net thickness and the netexposure surface area A of the net semipermeable body of the osmoticdelivery system 970 may be controlled by removing or addingsemipermeable body elements 983 of different and varying configurations,i.e., having varying thicknesses and varying exposed surface areas 948.

[0202] The embodiments of the present invention illustrated in FIGS.13-20 also allow an administrator to increase or decrease the releaserate of beneficial agent from the osmotic delivery system. For example,just prior to subcutaneous placement in a human patient, the beneficialagent release rate of an osmotic delivery system according to thepresent invention may be adjusted to accommodate for the body weight ofthe patient. The beneficial agent release rate may be adjusted as partof the implantation procedure. Additionally, it may be adjusted afterthe osmotic delivery device has been implanted and a physiological orefficacious response has been determined. Thus, the osmotic deliverysystems of the present invention may be used to obtain a specifictherapeutic response as the beneficial agent release rate from theosmotic delivery systems is predictable and adjustable.

[0203] FIGS. 21-28 illustrate features of osmotic delivery system plugsor semipermeable body assemblies 1030, 1030′, 2030, 2030′ according tofurther embodiments of the present invention. The plugs 1030, 1030′,2030, 2030′ each include a semipermeable body 1032, 1032′, 2032, 2032′having a recess 1052, 1052′, 2052, 2052′ that can receive an insert,similar to the inserts 60, 160 described above in connection with theplugs 30, 130 illustrated in FIGS. 4 and 12.

[0204] The osmotic delivery system plugs 1030, 2030 will be described inreference to exemplary osmotic delivery systems 1070, 2070 according toembodiments of the present invention illustrated in FIGS. 25 and 28. Theconfiguration of the osmotic delivery system plugs 1030, 2030 dictatesthe liquid permeation rate through the plugs, which generally controlsthe delivery rate of a beneficial agent 1072, 2072 from each of theosmotic delivery systems 1070, 2070.

[0205]FIG. 21 illustrates a side view of the osmotic delivery systemplug 1030. The plug 1030 is formed from a semipermeable body 1032. Thesemipermeable body 1032 includes a cylindrical portion 1031, and aconical portion 1033 located directly adjacent to the cylindricalportion 1031. The conical portion 1033 is in the shape of a rightcircular cone having a cone-shaped surface 1048, a vertex 1049, and acone base 1041. The vertex 1049 of the cone-shaped surface 1048 islocated opposite from the cylindrical portion 1031 and the base 1041 ofthe conical portion. When positioned in the enclosure of an osmoticdelivery system 1070, the vertex faces away from the osmotic agent 1078.As shown in FIG. 21, the vertex 1049 is a rounded or smoothed point.

[0206] The semipermeable body 1032 includes means for sealing or ribs1034 that extend away from the outer surface 1038 of cylindrical portionof the plug. The ribs 1034 are located at the cylindrical portion 1031of the semipermeable body 1032. The ribs 1034 are the means by which theplug 1030 operates like a cork or stopper, obstructing and plugging anopening 1079 in the enclosure 1071 of the osmotic delivery system 1070illustrated in FIG. 25. The semipermeable body 1032 is, therefore,intended for at least partial insertion into the opening 1079 of theenclosure 1071. The ribs 1034 seal the environment of use from an insideof the enclosure 1071 to prevent liquid and other substances in theenvironment of use, besides the permeation liquid, from entering theosmotic delivery system 1070 while also preventing materials from theinside of the delivery system from leaking or escaping to theenvironment of use.

[0207] As illustrated in FIGS. 21 and 25, the cylindrical portion 1031having the ribs 1034 is intended for at least partial insertion in anosmotic delivery system opening 1079. The plug 1030 is partially orentirely insertable into the opening 1079. Because at least a portion ofthe plug 1030 is in contact with the interior surface of the enclosure1071, and has means for sealing 1034, only a portion of the entireexterior surface of the semipermeable body 1032 is immediately exposedto liquids in the environment of use. In the embodiment of the presentinvention illustrated in FIGS. 21-25, the cone-shaped or conical surface1048 of the conical portion 1033 is the exposure surface or liquidcontact surface, i.e., that portion of the semipermeable body which isimmediately exposed to liquids when the osmotic delivery system isplaced in a liquid environment of use. Thus, the cylindrical portion1031 is not immediately exposed to liquids when the osmotic deliverysystem 1070 is placed in a liquid environment of use, while the conicalportion 1033 is immediately exposed to liquids when the osmotic deliverysystem 1070 is placed in a liquid environment of use.

[0208] Although the osmotic delivery system plug 1030 includes the ribs1034 to help form a seal between the enclosure 1071 and thesemipermeable body 1032, other embodiments of the invention need notinclude the ribs 1034. For example, as illustrated in FIG. 26, theosmotic delivery system plug 2030 has a semipermeable body 2032 havingan exterior surface 2048 that is smooth, entirely conical-shaped, andvoid of any ribs. In such an embodiment, an adhesive and/or aninterference fit between the plug 2030 and the enclosure of the osmoticdelivery system can be used to form the aforementioned seal between theenclosure and semipermeable body 2032. Thus, at least the base 2041 ofthe cone-shaped semipermeable body 2032 has a diameter that is greaterthan the internal diameter of the enclosure into which the body is to beinserted to help effect a seal between the semipermeable body and theenclosure. A portion of the conical exterior surface 2048 of thesemipermeable body 2032 contacts the interior surface of the enclosureto define the seal between the enclosure and the semipermeable body. Theportion of the conical exterior surface 2048 that contacts the interiorsurface of the enclosure 2071 is not immediately exposed to liquid whenan osmotic delivery system incorporating the plug 2030 is located in aliquid environment of use. The portion of the conical exterior surface2048 that does not contact the interior surface of the enclosure isimmediately exposed to liquid when an osmotic delivery systemincorporating the plug 2030 is located in an liquid environment of use.

[0209] Additionally, it is not necessary that the osmotic deliverysystem plug 1030 include the cylindrical portion 1031. As illustrated inFIGS. 26 and 27, the osmotic delivery system plugs 2030, 2030′ include asemipermeable body 2032, 2030′ that is entirely cone-shaped.

[0210] As illustrated by FIG. 27, the conical-shaped semipermeable body2032′ may also include ribs 2034′ on the conical exterior surface 2048′of the body. As shown in FIG. 28, a plurality of the ribs 2034′ contactthe interior surface of the enclosure 2071 when the semipermeable body2032′ is inserted into the opening of the enclosure of the osmoticdelivery system 2070 according to another embodiment of the presentinvention. The base 2041′ of the cone-shaped semipermeable body 2032,2032′ has a diameter that is greater than the internal diameter of theopening into the enclosure through which the body is to inserted. Thus,as illustrated in FIG. 28, the base 2041′ of the cone-shapedsemipermeable body 2032′ deflects when the semipermeable body isinserted into the enclosure 2071.

[0211] The semipermeable bodies 2032, 2032′ illustrated in FIGS. 26-28include a conical recess or cone-shaped hollow portion 2052, 2052′.Because the base 2041, 2041′ of the semipermeable body 2032, 2032′deflects when it is inserted into the enclosure 2071, the shape of theconical recess 2052, 2052′ also changes. In the osmotic delivery system2070, the semipermeable body 2032′ has only been partially inserted intothe enclosure 2071. Hence, a portion of the semipermeable body extendsout of the enclosure 2071. The portion of the conical exterior surface2048′ that is not in contact with the enclosure 2071 and faces away fromthe osmotic agent 2078 will be immediately exposed to liquids when theosmotic delivery system is located in a liquid environment of use.

[0212] As shown in FIG. 25, the osmotic delivery system plug 1030 can belocated entirely within the enclosure 1071 such that the cone-shapedsurface 1048 is also located entirely within the enclosure 1071. Theplug 1030 may be inserted entirely through an opening 1079 of theenclosure 1071 of the osmotic delivery system 1070 because the plug 1030does not include a stop surface or head preventing complete insertion,such as the stop surface 36 illustrated in FIG. 2. When the plug 1030 iscompletely inserted within the enclosure 1071 of the osmotic deliverysystem, the cone-shaped surface 1048 defines the liquid or exposuresurface of the plug because it is immediately exposed to liquids whenthe an osmotic delivery system 1070 is placed in a liquid environment ofuse. The plug 1030 may also be partially inserted into the opening 1079of an osmotic delivery system enclosure 1071 such that a portion of theconical liquid contact surface 1048 is external of the enclosure 1071.

[0213] As illustrated by the osmotic delivery system 2070 shown in FIG.28, the delivery port 2075 is not directly formed in the wall of theenclosure 2071, but is instead located in a flow moderator or flowmodulator device 2073. The flow modulator device 2073 is a plug-likemember having a liquid flow path, such as the illustrated spiraldelivery channel, through which beneficial agent can travel to exit theenclosure 2071. Such flow modulator devices are described in U.S. patentapplication Ser. No. 08/595,761, the entire disclosure of which isincorporated herein by reference. The flow modulator device 2073closes-off one open end of a cylindrical tube to define the enclosure2071. In this respect, the enclosure 2071 has a delivery port 2075.

[0214] As illustrated by FIG. 28, the cylindrical wall of the enclosure2071 has two openings located opposite from each other and eachconfigured to receive the flow moderator device 2074 and the osmoticdelivery system plug 2030′. Thus, the enclosure 2071 includes acylindrical tube having two opposing openings into the cylindrical tube.It will be appreciated that the plug 2030′, as well as the previouslydescribed osmotic delivery system plugs 30, 130, 1030, 1030′, 2030,2030′ can be inserted through either of the openings into the interiorof the enclosure 2071. For example, in assembling the osmotic deliverydevice 2070 according to one embodiment of the present invention, theplug 2030′ is inserted “vertex first” through an opening into theenclosure 2071. Once the osmotic agent tablet 2078 has been formed, itis placed inside the enclosure 2071 through the same opening such thatthe tablet is adjacent to the plug 2030′. Then, the separating member2074 is inserted through the same opening so that the separating member2074 is on the side of the osmotic tablet 2078 opposite from the plug2030′. The enclosure 2071 is then filled with the beneficial agent 2072and the flow moderator device 2073 is placed into the same opening ofthe enclosure 2071 to close off and seal the osmotic delivery system.

[0215]FIG. 23A and 23B depict the cross-sections of semipermeable bodies1032, 1032′ according to the present invention. The semipermeable bodies1032, 1032′ each include a hollow interior portion or recess 1052,1052′. In the embodiment of the present invention depicted in FIG. 23A,the recess 1052 is cylindrically shaped. The recess 1052 has acylindrical and longitudinal interior surface 1054 which begins at aninsert opening 1055 formed by the recess in the insert end 1056 of thesemipermeable body 1032, and ends at a depth surface 1050 within thebody 1032. Because of the cylindrical shape of the cylindrical portion1031 of the semipermeable body 1032 and the cylindrical shape of therecess 1052, the body includes a cup-shaped region, where the “bottom ofthe cup” is conical and has a predetermined plug thickness t and thewall 1057 has a predetermined wall width w, similar to the plug 30illustrated in FIG. 4B.

[0216] As shown in FIG. 23A, the predetermined wall width w is definedby the location of the outer surface 1038 relative to the interiorsurface 1054, and the predetermined plug thickness t is defined by thelocation of the depth surface 1050 relative to the conical surface 1048.Because the conical surface 1048 slopes relative to the depth surface1050, the predetermined plug thickness t actually changes along theslope of the conical surface.

[0217] As described above in reference to the plug 30, the depth of thedepth surface 1050 within the semipermeable body 1032, and the distancethe interior surface 1054 is from the longitudinal center axis C (ordiameter 1046 of the recess 1052) determine the size of the hollowinterior portion 1052 in the interior of the semipermeable body 1032.Together, the predetermined wall width w and the predetermined plugthickness t define the effective thickness L of the semipermeable body1032. As described above, by varying the size of the recess or hollowinterior portion 1052, or, in other words, by varying the predeterminedplug thickness t and/or the predetermined wall width w, the effectivethickness L of the semipermeable body 1032 of the osmotic deliverysystem plug 1030 may also be varied. In this manner, the liquidpermeation rate through the body 1032 can be controlled.

[0218] For instance, by decreasing the effective thickness L of thesemipermeable body 1032 of the plug 30, the liquid permeation rate dV/dtthrough the plug may be increased. As illustrated in FIG. 23B, theeffective thickness L of the semipermeable body 1032′ may be decreasedby decreasing the predetermined plug thickness t′ of the semipermeablebody. This is achieved by increasing the size of the recess 1052.

[0219]FIG. 23B illustrates a preferred semipermeable body 1030′. Therecess 1052′ includes a cylindrical portion and a conical portion.Hence, the recess 1052′ is in the shape of a bullet and has a volumegreater than the cylindrical recess 1052. Alternatively, the recess 1052can be entirely conical, such as the recesses 2052, 2052′ shown in FIGS.26 and 27. The recess 1052′ generally follows the contours of the outersurface 1038 and cone-shaped surface 1048. The distance of the depthsurface 1050′ relative to the conical surface 1048′ is constant, and thedistance of the outer surface 1038′ relative to the interior surface1054′ is constant. Thus, the predetermined wall width w′ and thepredetermined plug thickness t′ are approximately equal and constant.Although not illustrated, the semipermeable bodies 1030, 2030 need notinclude a recess or hollow portion.

[0220]FIGS. 24 and 25 illustrate inserts 1060, 1060′ that can beincluded in an exemplary osmotic delivery plug 1030 or osmotic deliverysystem semipermeable body assembly in accordance with the presentinvention. As shown in FIG. 25, the insert 1060 is intended forinsertion into the cylindrical recess or hollow interior portion 1052.The insert 1060 can be inserted in the recess 1052 for assisting thesemipermeable body 1032 in effecting a seal with the interior of theenclosure 1071. In the embodiment of the present invention illustratedin FIG. 25, the insert 1060 is cylindrically shaped to match the shapeof the hollow interior portion 1052, similar to the insert 60 shown inFIGS. 5 and 6. The insert 1060 may be in any number of different shapesand sizes. For example, the insert can be entirely conical, or asillustrated by FIG. 24, the insert 1060′ can be bullet-shaped. Thus, theinsert 1060′ includes a conical portion 1063′ and a cylindrical portion1061′. In the embodiments of the present invention illustrated in FIGS.26 and 27, an insert (not illustrated) may be received by the recesses2052, 2052′. As described above, because the semipermeable body 2032,2032′ will deflect upon insertion into the enclosure 2071, the insertcan be volumetrically smaller than the recess 2052, 2052′ and/or shapeddifferently than the recess 2052, 2052′ to accommodate the deflection ofthe semipermeable body toward the interior of the enclosure 2071, whilestill assisting in effecting a seal between the enclosure and thesemipermeable body 2032, 2032′. The insert 1060′ shown in FIG. 24 can bereceived by a substantially identically shaped cone-shaped recess 1052′.The inserts 1060, 1060′ can be fabricated from the same materials as thepreviously described insert 60.

[0221] Depending upon the application, the osmotic delivery system plugs1030, 2030 need not include an insert. For example, in somecircumstances and even if the semipermeable body includes a recess, theseal formed between the enclosure and the semipermeable body (without aninsert therein) is sufficient to seal the environment of use from aninside of the enclosure to prevent liquid and other substances in theenvironment of use, besides the permeation liquid, from entering theosmotic delivery system while also preventing materials from the insideof the delivery system from leaking or escaping to the environment ofuse.

[0222] As described earlier, the beneficial delivery rate dMt/dt througha semipermeable body may be approximated by the following formula:

dMt/dt=dV/dt•C={P A Δπ/L}•C

[0223] For a selected membrane material, osmotic agent, and beneficialagent concentration, and thickness L, the liquid permeation rate dV/dtthrough the membrane is directly proportional to the liquid surface areaA of the membrane body.

[0224] The liquid surface area A_(c) of the conical surface 1048, 1048′,2048, 2048′ is approximately equal to πr(r²+h²)^(½), where “r” is theradius at the base of the conical surface and “h” is the height of theconical surface.

[0225] When the osmotic delivery system plug 130 (see FIG. 12) iscompletely inserted into an opening of an enclosure of an osmoticdelivery system, such as the opening 2079 shown in FIG. 28, the flatcircular surface 148 is the liquid contact surface or exposure surface,i.e., the surface that is immediately exposed to liquid when the osmoticdelivery system is located in its environment of use. The surface areaA_(o) of the flat circular surface 148 is equal to πr². In contrast, thesurface area A_(c) of the cone-shaped surface 1048, 1048′, 2048, 2048′is equal to πr(r²+h²)^(½).

[0226] One skilled in the art will appreciate that when the plugs 130,1030 are completely inserted into openings of identical enclosures, theexposure surface area A_(c) of the conical surface 1048 is greater thanthe exposure surface area A_(o) of the circular surface 148 (assumingthat the radius r, which generally corresponds to the internal diameterof the enclosure 1071, is the same for both semipermeable bodies). Forexample, FIG. 29 is a graph illustrating the theoretical increase insurface area A_(c) (mm²) for a conical surface of a semipermeable body(such as the conical surface 1048 of the semipermeable body 1032), andthe theoretical increase in surface area A_(o) (mm²) for a flat circularsurface of a semipermeable body (such as the flat circular surface 148of the semipermeable body 132), as the diameter of the base of theconical surface and the diameter (mm) of the flat circular surfacecorrespondingly increase. The curves illustrated in FIG. 29 are based onthe above-described surface area equations for A_(c) and A_(o). As shownby FIG. 29, the surface area A_(c) for the conical surface is greaterthan the surface area A_(o) of the circular surface at all diameters.

[0227] Because the surface area A_(c) of the conical surface 1048 isgreater than that of the flat circular surface 148, the liquidpermeation rate through the semipermeable body 1030 will be greater thanthat through the semipermeable body 130 (assuming that the semipermeablebodies 130, 1030 have roughly the same effective thickness L).Accordingly, the liquid permeation rate through the semipermeable bodiesof the present invention may be increased by increasing the surface areaA of the semipermeable body that is immediately exposed to liquids uponinsertion of the osmotic delivery system in an liquid environment ofuse. For example, FIG. 30 illustrates the theoretical increase inbeneficial agent release rate dMt/dt (μl/hour) from an osmotic deliverysystem having a semipermeable body having a conical surface area A_(c)(such as that illustrated in FIG. 23B) as the diameter of thesemipermeable body increases. FIG. 30 also generally illustrates theactual increase in beneficial agent release rate dMt/dt (μl/hour) froman osmotic delivery system having a semipermeable body having a flatcircular surface area A_(o) (such as that illustrated in FIG. 12) as thediameter of the semipermeable body increases. The calculations used toobtain the curves shown in FIG. 30 assume that both semipermeable bodiesare completely inserted within an enclosure of an osmotic deliverysystem.

[0228] The curve illustrated in FIG. 30 corresponding to thesemipermeable membrane body having a flat circular surface area A_(o)was obtained by testing an osmotic delivery system having asemipermeable membrane body similar to that illustrated in FIG. 12(formed from PEBAX 23, having a 23 mil thickness, and a 10.5% radialclearance where radial clearance is the amount of pressure it takes topush the semipermeable membrane body out of the enclosure as measured bythe ratio of the ID of the enclosure divided by the OD of the membraneexpressed as a percentage). The curve illustrated in FIG. 30corresponding to the semipermeable membrane body having a conicalsurface area A_(c) was obtained by theoretically estimating how much thebeneficial agent release rate dMt/dt would increase (based on theequations: A_(c)=r(r²+h²)^(½) and dMt/dt=dV/dt•C={P A Δπ/L}•C) if theflat circular surface area A_(o) were increased to the conical surfacearea A_(c) as shown in FIG. 29 for a given diameter. As FIG. 30illustrates, because the surface area A_(c) of a conical surface isgreater than that of a flat circle, the liquid permeation rate through asemipermeable body having a conical surface will be greater than thatthrough a semipermeable body having only a flat circular surface.Accordingly, the liquid permeation rate through the semipermeable bodiesof the present invention may be increased by increasing the surface areaA of the semipermeable body that is immediately exposed to liquids uponinsertion of the osmotic delivery system in an liquid environment ofuse.

[0229] The surface area A that is immediately exposed to liquids may beincreased by manufacturing the exposure or liquid contact surface in aconical shape, a spherical shape, or other configurations that have agreater surface area than that of a flat disk. In this manner, theliquid permeation rate through the semipermeable membrane body may befurther increased.

[0230] In many instances, it is desirable to increase the beneficialagent delivery rate dMt/dt from osmotic delivery systems. For example,osmotic delivery systems destined for animal implantation often must beable to release all of the beneficial agent within a short period oftime, such as one week or even a few days. As described earlier, thebeneficial agent delivery rate dMt/dt may be increased by increasing theosmotic pressure difference between the osmotic agent and the liquid onthe other side of the membrane, and by varying the liquid permeabilitycoefficient P of the semipermeable material. Depending upon the specificapplication, it may not be possible to further increase the beneficialagent delivery rate dMt/dt by varying the permeability coefficient P orthe osmotic pressure difference Δπ. Additionally, it may not be possibleto further increase the liquid permeation rate through the semipermeablemembrane (to increase beneficial agent delivery rate dMt/dt) bydecreasing the effective thickness L of the semipermeable membrane bodywithout jeopardizing the structural integrity and sealingcharacteristics of the semipermeable membrane body. Thus, in thesecircumstances it is desirable to increase the liquid permeation ratethrough the semipermeable body without substantially decreasing theeffective thickness L of the semipermeable body.

[0231] As set forth above, the liquid permeation rate through thesemipermeable membrane bodies of the present invention may be increasedby increasing the surface area A of the semipermeable body that isimmediately exposed to liquid when the osmotic delivery system islocated in a liquid environment of use. For example, the exposuresurface area A may be increased by forming the conical portion 1033 onthe semipermeable body 1032. Because the exposure surface area A_(c) ofthe cone-shaped surface 1048 is greater than the exposure surface areaA_(o) of the flat circular surface 148, the liquid permeation ratethrough the semipermeable membrane 1032 is greater than that of thesemipermeable membrane 132. Hence, the beneficial agent delivery ratedMt/dt may be increased by increasing the surface area A of thesemipermeable body that is immediately exposed to liquids when theosmotic delivery system is located in a liquid environment of use.

[0232] In the above described manner, the liquid permeation rate dV/dtthrough the membrane plugs 1030, 1030′, 2030, 2030′ can be increased,permitting faster beneficial agent delivery rates from osmotic deliverysystems according to the present invention. This is further advantageousbecause low liquid uptake membrane materials can be used to fashionosmotic delivery system plugs 1030, 1030′, 2030, 2030′ according to thepresent invention with fast liquid permeation rates. Such fastpermeation rates were previously achieved by fashioning membrane plugsfrom high liquid uptake and possibly biologically unstable membranematerials, which occasionally permit items in the interior of theosmotic delivery system to leak to the environment of use.

[0233] The osmotic delivery system plugs 1030, 1030′, 2030, 2030′ permitthe administration of beneficial agents from osmotic delivery systems atrapid delivery rates over a relatively short period of time, even thoughthe plugs may use a semipermeable material which, as measured againstprevious membrane plugs, has a low permeability coefficient. These lowpermeability coefficient membrane materials do not have high liquiduptake characteristics, and do not swell as dramatically as high uptakematerials when liquid from the surrounding environment permeates throughthe membrane. Thus, the osmotic delivery plugs 1030, 1030′, 2030, 2030′that each include a hollow interior portion 1052, 1052′, 2052, 2052′ anda cone-shaped surface 1048, 1048′, 2048, 2048′ configured for a fastliquid permeation rate, do not overly swell and creep out of thecapsule, or permit the osmotic agent to leak from the capsule.Furthermore, the osmotic delivery plug 1030, 1030′, 2030, 2030′ can bemade from materials that are stable in biological environments, and donot significantly degrade over time, which could permit fluids,crystals, or powder within the interior of the enclosure to leak to theenvironment of use.

[0234] Another benefit of controlling the surface area A, as well as theeffective thickness L, of the osmotic delivery system plugs 1030, 1030′,2030, 2030′ is that different liquid permeation rates are obtainablefrom the same semipermeable material having a set permeabilitycoefficient. A different membrane material need not be used for everysystem which has a different desired beneficial agent delivery rate, andbiocompatibility and toxicity tests need only be performed on onesemipermeable material.

[0235] In the above described manner, the liquid permeation rate throughhe semipermeable membrane bodies 32, 132, 232, 332, 432, 632, 732, 732,832, (932, 932′, 932″), 1032, 1032′, 2032, 2032′ can be controlled inthe osmotic delivery devices illustrated in FIGS. 7, 13-20, 25 and 28.This is especially advantageous because one membrane material can beused for the semipermeable bodies, while still permitting the liquidpermeation rate to be controlled or varied. Additionally, as describedabove, by varying the “effective thickness” L and/or the exposuresurface area A of the semipermeable bodies, the liquid permeation ratethrough the semipermeable bodies, and hence the delivery rate of thebeneficial agent from the osmotic delivery system can be controlled.This is beneficial because for example, different desired liquidpermeation rates through the semipermeable bodies are obtainable fromsemipermeable bodies formed from the same material having the samepermeability coefficient and liquid uptake characteristics. This isfurther beneficial because biocompatibility and toxicity tests need onlybe performed on one semipermeable material. Moreover, it is especiallydesirable that the beneficial agent delivery rate from the osmoticdelivery system be easily controlled by simply varying the liquidpermeation rate through the semipermeable body of any one of thealternative embodiments of the present invention described above.

[0236] While the invention has been described in detail with referenceto a preferred embodiment thereof, it will be apparent to one skilled inthe art that various changes can be made, and equivalents employedwithout departing from the spirit and scope of the invention.

We claim:
 1. An osmotic delivery system plug for controlling a deliveryrate of a beneficial agent in an osmotic delivery system, the plugcomprising: a semipermeable body having: a recess having an interiorsurface beginning at an opening in the body and ending at a depthsurface within the semipermeable body; a liquid contact surface locatedopposite the depth surface; an outer surface located opposite theinterior surface, the outer surface having means for sealing anenvironment of use from an inside of an enclosure of an osmotic deliverysystem in which the body is insertable; a predetermined plug thicknessdefined by the location of the depth surface relative to the liquidcontact surface; and a predetermined wall width defined by the locationof the outer surface relative to the interior surface, at least one ofthe predetermined plug thickness and predetermined wall width forcontrolling a rate of liquid permeation through the semipermeable body.2. The osmotic delivery system plug according to claim 1 furthercomprising an insert located within the recess.
 3. The osmotic deliverysystem plug according to claim 2 , wherein the insert is pervious toliquids.
 4. The osmotic delivery system plug according to claim 1 ,wherein the insert includes a top surface adjacent the depth surface ofthe tubular interior.
 5. The osmotic delivery system plug according toclaim 1 , wherein the insert includes a peripheral surface mating theinterior surface of the recess.
 6. The osmotic delivery system plugaccording to claim 1 , wherein the liquid contact surface of thesemipermeable body includes a cone-shaped surface.
 7. An osmoticdelivery system plug for controlling a delivery rate of a beneficialagent in an osmotic delivery system comprising: a semipermeable body atleast partially positionable in an opening in an enclosure of an osmoticdelivery system, the semipermeable body including a hollow interiorportion having a size selected to obtain a predetermined liquidpermeation rate through the semipermeable body, the liquid permeationrate for controlling a delivery rate of a beneficial agent in an osmoticdelivery system.
 8. The osmotic delivery system plug according to claim7 , wherein the hollow interior portion is conical.
 9. The osmoticdelivery system plug according to claim 7 , wherein the hollow interiorportion is cylindrical.
 10. The osmotic delivery system plug accordingto claim 7 , wherein the semipermeable body includes a liquid contactsurface for contacting a liquid external of the osmotic delivery system.11. The osmotic delivery system plug according to claim 10 , wherein theliquid contact surface is located at an end of said body opposite thehollow interior portion.
 12. The osmotic delivery system plug accordingto claim 11 , wherein the hollow interior portion includes a depthsurface defining a plug thickness of the semipermeable body between theliquid contact surface and the depth surface.
 13. The osmotic deliverysystem plug according to claim 10 , wherein the liquid contact surfaceis cone-shaped.
 14. The osmotic delivery system plug according to claim7 , including an insert located within the hollow interior portion. 15.The osmotic delivery system plug according to claim 14 , wherein thehollow interior portion and the insert are cylindrical, the cylindricalhollow interior portion matingly receiving the cylindrical insert. 16.The osmotic delivery system plug according to claim 14 , wherein theinsert is pervious to liquids.
 17. The osmotic delivery system plugaccording to claim 14 , wherein the insert is a semipermeable materialhaving a different permeability than that of the semipermeable body. 18.The osmotic delivery system plug according to claim 14 , wherein theinsert includes an osmotic agent.
 19. The osmotic delivery system plugaccording to claim 7 , wherein the semipermeable body includes an outersealing surface for effecting a seal with the enclosure when the body isat least partially positioned in the enclosure.
 20. The osmotic deliverysystem plug according to claim 19 , wherein the hollow interior portionincludes an interior surface defining a wall width between the outersealing surface and the interior surface.
 21. The osmotic deliverysystem plug according to claim 19 , including a liquid pervious memberlocated within the hollow interior portion for assisting in effectingthe seal.
 22. The osmotic delivery system plug according to claim 19 ,wherein the outer sealing surface includes at least one rib.
 23. Anosmotic delivery system comprising: an enclosure having an opening and adelivery port, said enclosure having an interior holding a liquidswellable osmotic agent and a beneficial agent, said liquid swellableosmotic agent for imbibing liquid from a surrounding environment andcausing a delivery rate of said beneficial agent from said enclosure; aplug having a semipermeable body at least partially positioned in theopening, the semipermeable body including a hollow interior portionhaving a size selected to obtain a predetermined liquid permeation ratethrough the semipermeable body, the liquid permeation rate forcontrolling the delivery rate of the beneficial agent in the osmoticdelivery system.
 24. The osmotic delivery system according to claim 23 ,further comprising a separating member positioned in the enclosurebetween the osmotic agent and the beneficial agent.
 25. The osmoticdelivery system according to claim 24 , wherein the separating member isa movable piston.
 26. The osmotic delivery system according to claim 23, wherein the osmotic agent is a tablet.
 27. The osmotic delivery systemaccording to claim 23 , wherein the plug includes an insert located inthe hollow interior portion.
 28. The osmotic delivery system accordingto claim 23 , wherein the enclosure is substantially impermeable toliquids.
 29. The osmotic delivery system according to claim 23 , whereinthe semipermeable body includes a cone-shaped surface.
 30. A method ofcontrolling a delivery rate of a beneficial agent from an osmotic drugdelivery system that includes an enclosure having an interior holding aliquid swellable osmotic agent and a beneficial agent, the osmotic drugdelivery system also including a plug having a semipermeable body atleast partially positioned in an opening of an enclosure, thesemipermeable body including a hollow interior portion, the methodcomprising the steps of: determining a desired delivery rate of thebeneficial agent; selecting a plug with a hollow interior portion sizedto obtain a predetermined liquid permeation rate through thesemipermeable body corresponding to the desired delivery rate of thebeneficial agent; positioning the plug at least partially within theopening of the enclosure; and locating the osmotic drug delivery systemin an environment of use.
 31. The method according to claim 30 , furtherincluding the step of locating an insert within the hollow interiorportion.
 32. A method of changing a liquid permeation rate through asemipermeable body of an osmotic delivery system to increase a deliveryrate of a beneficial agent from the osmotic delivery system, the methodcomprising the steps of: making a semipermeable body having a liquidpermeability coefficient and a thickness; and changing said thickness ofsaid semipermeable body to alter a liquid permeation rate through saidsemipermeable body.
 33. The method according to claim 32 , wherein saidsemipermeable body is located in an opening of the osmotic deliverysystem.
 34. The method according to claim 32 , wherein said thickness ofsaid semipermeable body is changed by cutting said semipermeable body.35. The method according to claim 32 , wherein said thickness is changedafter said semipermeable body has been inserted into an opening of theosmotic delivery system.
 36. The method according to claim 32 , whereina liquid impermeable sleeve surrounds a cylindrical surface of saidsemipermeable body, further comprising the step of changing a length ofsaid liquid impermeable sleeve.
 37. The method according to claim 36 ,wherein said length of said semipermeable sleeve is changed when saidthickness of said semipermeable body is changed.
 38. The methodaccording to claim 32 , wherein said semipermeable body is located atleast partially within an enclosure of said osmotic delivery system andan enclosure length of said enclosure is changed when said thickness ofsaid semipermeable body is changed.
 39. A method of varying a liquidpermeation rate through a semipermeable body of an osmotic deliverysystem in which a liquid impermeable sleeve is mounted on thesemipermeable body to vary a delivery rate of a beneficial agent fromsaid osmotic delivery system, the method comprising the step of movingsaid liquid impermeable sleeve along an exterior surface of saidsemipermeable body to vary an amount of surface area of said exteriorsurface that is immediately exposed to liquids when said osmoticdelivery system is located in a liquid environment of use.
 40. Themethod according to claim 39 , wherein said semipermeable body is atleast partially located within an enclosure of said osmotic deliverysystem, and said exterior surface is a cylindrical surface of saidsemipermeable body.
 41. The method according to claim 39 , wherein saidliquid impermeable sleeve is moved along an enclosure exterior surfaceof an enclosure of said osmotic delivery system when said liquidimpermeable sleeve is moved along said exterior surface of saidsemipermeable body.
 42. A method of varying a liquid permeation ratethrough a semipermeable body of an osmotic delivery system to vary adelivery rate of a beneficial agent from the osmotic delivery system,the method comprising the step of: selecting a desired liquid permeationrate through the semipermeable body of the osmotic delivery system; andproviding a plurality of semipermeable body elements in abuttingrelation to one another to define said semipermeable body and to achievesaid selected liquid permeation rate.
 43. The method according to claim42 , further comprising the step of adding an additional semipermeablebody element in abutting relation to said plurality of saidsemipermeable body elements to achieve another liquid permeation ratedifferent than said selected liquid permeation rate.
 44. The methodaccording to claim 42 , further comprising the step of removing at leastone of said semipermeable body elements from said plurality of saidsemipermeable body elements to achieve another liquid permeation ratedifferent than said selected liquid permeation rate.
 45. The methodaccording to claim 42 , wherein said plurality of semipermeable bodyelements are attached to each other with an adhesive.
 46. An osmoticdelivery system comprising: a liquid impermeable enclosure having aninterior holding a beneficial agent and an osmotic agent for imbibingliquid from a surrounding environment and causing delivery of saidbeneficial agent from said liquid impermeable enclosure; a semipermeablebody in liquid communication with said liquid impermeable enclosure forpermitting liquid to permeate through said semipermeable body to saidosmotic agent; a liquid impermeable sleeve separate from said liquidimpermeable enclosure and surrounding a portion of a surface of saidsemipermeable body such that said portion of said surface is notimmediately exposed to liquid when said osmotic delivery system islocated in a liquid environment of use and such that said semipermeablebody includes an exposure surface defined by an area of said surfacethat is not surrounded by said liquid impermeable sleeve and isimmediately exposed to liquids when said osmotic delivery system islocated in the liquid environment of use.
 47. The osmotic deliverysystem according to claim 46 , wherein said portion of said surface ofsaid semipermeable body is a cylindrical surface and said liquidimpermeable sleeve abuts against said cylindrical surface.
 48. Theosmotic delivery system according to claim 47 , wherein the exposuresurface of said semipermeable body includes a surface incident to saidcylindrical surface.
 49. The osmotic delivery system according to claim46 , wherein said liquid impermeable sleeve abuts said surface of saidsemipermeable body and is movable with respect to said surface to varyan amount of said exposure surface that is exposed to liquid when saidosmotic delivery system is placed in the liquid environment of use. 50.The osmotic delivery system according to claim 46 , wherein said liquidimpermeable sleeve abuts against an exterior surface of said liquidimpermeable enclosure and is movable with respect to said exteriorsurface of said liquid impermeable enclosure.
 51. The osmotic deliverysystem according to claim 46 , wherein the semipermeable body ispositioned within an opening of said liquid impermeable enclosure ofsaid osmotic delivery system.
 52. The osmotic delivery system accordingto claim 46 , wherein at least one of said liquid impermeable sleeve andsaid enclosure includes threads such that said liquid impermeable sleeveis movable linearly with respect to said enclosure by rotating saidsleeve.
 53. An osmotic delivery system comprising: an enclosure havingan interior holding a beneficial agent and an osmotic agent, saidosmotic agent for imbibing liquid from a surrounding environment andcausing delivery of said beneficial agent from said enclosure; a firstsemipermeable body in liquid communication with said enclosure forpermitting liquid to permeate through said first semipermeable body tosaid osmotic agent; and a second semipermeable body abutting said firstsemipermeable body and in liquid communication with said firstsemipermeable body so as to permit liquid to permeate through said firstsemipermeable body and said second semipermeable body to said osmoticagent.
 54. The osmotic delivery system according to claim 53 , whereinsaid second semipermeable body is removable from said firstsemipermeable body to vary a liquid permeation rate into said osmoticdelivery system.
 55. The osmotic delivery system according to claim 53 ,wherein said second semipermeable body is attached to said firstsemipermeable body by an adhesive.
 56. The osmotic delivery systemaccording to claim 53 , wherein said first semipermeable body and saidsecond semipermeable body are semipermeable layers.
 57. An osmoticdelivery system comprising: an enclosure having an opening and adelivery port, said enclosure having an interior holding a liquidswellable osmotic agent and a beneficial agent, said liquid swellableosmotic agent for imbibing liquid from a surrounding environment andcausing a delivery rate of said beneficial agent from said enclosure;and a plug having a semipermeable body, the plug being at leastpartially positioned in the opening, the semipermeable body having anexposure surface that is immediately exposed to liquids when the osmoticdelivery system is located in a liquid environment of use, said exposuresurface including a conical surface.
 58. The osmotic delivery systemaccording to claim 57 , wherein the semipermeable body includes acylindrical portion.
 59. The osmotic delivery system according to claim57 , wherein a vertex of the conical surface faces away from the osmoticagent.
 60. The osmotic delivery system according to claim 57 , whereinthe semipermeable body includes ribs for effecting a seal between theenclosure and the semipermeable body.
 61. The osmotic delivery systemaccording to claim 57 , the semipermeable body including a hollowinterior portion having a size selected to obtain a predetermined liquidpermeation rate through the semipermeable body, the liquid permeationrate for controlling the delivery rate of the beneficial agent in theosmotic delivery system.
 62. The osmotic delivery system according toclaim 61 , further comprising a porous insert located in the hollowinterior portion.